tag:blogger.com,1999:blog-87151617625556081312024-02-14T15:54:23.790-05:00Virology tidbitsMusings on Research related to Virusesthelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.comBlogger89125tag:blogger.com,1999:blog-8715161762555608131.post-48371239145806236042017-01-27T13:21:00.001-05:002017-01-30T15:00:23.161-05:00Impairment of neurogenesis in ZIKV infected neuronal cells: strain specific ? Asian/American v. African strains <div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">During the current Zika
Virus (ZIKV) outbreaks in the Americas, an increased number of cognitive
malformations including but not limited to microcephaly in foetuses and
neonates of mothers who had been infected with ZIKV during pregnancy, lead to
the conclusion that ZIKV might be neuroteratogenic, a hypothesis that has been supported by
findings that various ZIKV strains –including isolates from Asia such ZIKV SZ
01, ZIKV FSS13025 and H/PF/2013 as well as isolates from the Americas such as
ZIKV Mex 1-144, ZIKV PRV ABC059 and ZIKV
BR Paraiba 2015 or the (original) African isolate ZIKV MR766- not only infect
and replicate in neuronal cells in vitro and in vivo, but also induces
apoptosis of infected and non-infected cells. These results suggest that ZIKV
may cause abnormal neuronal development of the foetal brain by inducing cell
death of infected cells via intrinsic apoptosis as well as bystander apoptosis
of non-infected cells via the secretion of pro-inflammatory cytokines. <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span lang="EN-US">As described before, ZIKV
MR766 infected human neuronal progenitor cells (hNPC), not only undergo
apoptosis, but also are arrested at G2/M phase of the cell cycle as measured by
single parameter flow cytometry, which is supported by findings that in ZIKV
Mex 1-144 infected foetal brain tissue of mice a decrease in Ki67 positive and
Histone H3-P (Ser-10) positive cells can be observed, suggesting that ZIKV
infection arrests infected cells in G2 phase of the cell cycle. Further
research however is need if ZIKV infection of proliferating neuronal cells also
induces aberrant mitosis like Coronavirus infected Vero and primary chicken
cells. Moreover, the infection of </span>human i90c16 (induced pluripotent human neural stem
cell that are derived from IMR-90 human lung fibroblast cells with ZIKV
H/PF/2013 may induce genotoxic stress resulting in the formation of <span style="background-color: white; color: #05294a;">γH2AX (H2AX-Ser19) positive DNA damage repair foci;
since in ZIKV MR766 infected hNPC genes encoding for proteins that are involved
in the repair of DNA damage are downregulated, sustained presence of DNA damage
might result in the activation of the G2 checkpoint, thus preventing mitotic
entry. Change of the expression of genes related to the cellular DNA Damage
Response (DDR), apoptosis and neurogenesis may be induced in a TLR-3 dependent
manner since the infection of h9 derived human embryonic stem cells (hESC) with
ZIKV MR766 induces the activation of TLR-3 and thus TLR-3 mediated pathways
that downregulate the expression of genes related to neurogenesis and
upregulation of genes related to apoptosis. <o:p></o:p></span></span></div>
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<b><span style="background-color: white; color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">ZIKV BR AB_ES v. ZIKV MR766
induced apoptosis and the cell cycle<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></span></b></div>
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<span style="background-color: white; color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">In
the original study published by <a href="http://www.cell.com/cell-stem-cell/pdf/S1934-5909(16)00106-5.pdf">Tang <i style="mso-bidi-font-style: normal;">et al</i>. in 2016</a>, the authors infected
hNPC derived from dermal fibroblasts with ZIKV MR766, the original ZIKV isolate
from Uganda (1947) which was extensively passaged in mice in 1950s, and
analysed the changes in the expression of genes at 72 hrs p.i. . As described i<i style="mso-bidi-font-style: normal;">n extensio</i> <a href="http://virologytidbits.blogspot.com/2016/03/zika-virus-zikv-was-first-isolated-from.html">before</a>,
ZIKV MR766 downregulates the expression of genes encoding proteins involved in
the induction of DNA damage response pathways (HR, NHEJ and FA) as well as in
the initiation of DNA replication such as MCM-6 and the progression of the cell
cycle from G1 to S, S phase progression and mitosis. These results were
confirmed in a study in which dermal derived hNPC were infected with ZIKV MR766
or ZIKV FSS13025 with gene expression analysed at 64 hrs p.i.. Interestingly,
the latter study also identified genes involved in the repair of damaged DNA,
DNA replication and cell cycle progression that are only downregulated in ZIKV
FSS 13025 infected hNPC as well as genes that specifically upregulated in
either ZIKV MR766 or ZIKV FSS 13025 infected hNPC, suggesting that different
strains might alter the expression of a subset of genes in a strain specific
manner. Indeed, only ZIKV strains of the Asian lineage, ZIKV FSS 13025 and ZIKV
H/PF/2013 so far have been shown to induce p53. <o:p></o:p></span></span></div>
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<span style="background-color: white; color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">The
ZIKV strains that are currently circulating in the Americas are derived from
the Asian ZIKV lineage with ZIKV circulating in Brazil being 97-100% similar to
Asian isolates. The infection of hNPC derived from dermal fibroblasts with ZIKV
BR AB_ES for 72 hrs results in widespread apoptosis concomitant with the
activation of Caspase-3 and a reduction of the number of cells expressing the
neuronal markers Sox-2 and HUC/D, indicating reduction in the growth of
neurospheres, thus depleting the pool of neural progenitor cells. In contrast
to ZIKV MR766 infected hNPC however, the infection of hNPC with ZIKV BR AB_ES
does not induce a pronounced arrest in G2 phase of the cell cycle, suggesting
that ZIKV BR AB_ES -in contrast to ZIKV H/PF/2013 infected hNPC- might induce
apoptosis independent of cell cycle arrest. Further experiments are however
needed to determine if this is truly the cases since it might be possible that
infected cells arrest at G2 prior 72 hrs p.i.. Based on gene expression data,
both ZIKV MR766 and ZIKV BR AB_ES downregulate the expression of Cyclin E2
suggesting that both in ZIKV MR766 and ZIKV BR AB_ES infected hNPC the assembly
of the pre-replication complex at the DNA and the G1/S transition might be
affected. In addition, infection of hNPC with either ZIKV isolate downregulates
the expression of MCM-6, suggesting that DNA replication might be inhibited. In
contrast to ZIKV MR766, ZIKV BR AB_ES infection of hNPC upregulates the
expression of components of the DDR, namely FANCD2, BRCA1, and MRE11A as well
inducing the expression of DRAM-1 (probably via the induction of p53),
suggesting that at least some DDR pathways might be not affected by ZIKV BR
AB_ES. <o:p></o:p></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhv2RdfSY45Azct0HvOjNHFCzTdmN1M4O7Y9QiB_tc8jBYh97v0WDHhDO_9lA0md3McB3xTubm6l0zIWwS2CUK45-ZtuUHIu_6h9Ceoi6I2TVuUEP3sgz8Pqv2Oyb956WG4T-z7CeJNLk0Q/s1600/Presentation.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhv2RdfSY45Azct0HvOjNHFCzTdmN1M4O7Y9QiB_tc8jBYh97v0WDHhDO_9lA0md3McB3xTubm6l0zIWwS2CUK45-ZtuUHIu_6h9Ceoi6I2TVuUEP3sgz8Pqv2Oyb956WG4T-z7CeJNLk0Q/s640/Presentation.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Differences between ZIKV BR AB_ES and ZIKV MR766: DNA replication and cell cycle </td></tr>
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<span style="background-color: white; color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">In
addition to differences in the expression pattern of genes related to the
control of the cell cycle and the DDR, genes that have proposed to be involved
in viral replication are upregulated in hNPC infected with ZIKV BR AB_ES
compared with previously published data obtained from hNPC ZIKV MR766 infected
cells. <o:p></o:p></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjB9chKTHh2VenYbyZlfiXcBIv9hsz3SGj0Aa7C4SbX1XUC__Mlpj-XR5zokDAKwmaRnkWt7ypKAkzxRu-fENhuDKT4vGUUejgmhBXzgRZwPHMk9AxOpHKTHROPcaRzq1T9NH3PoqjNXGKh/s1600/Presentation.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjB9chKTHh2VenYbyZlfiXcBIv9hsz3SGj0Aa7C4SbX1XUC__Mlpj-XR5zokDAKwmaRnkWt7ypKAkzxRu-fENhuDKT4vGUUejgmhBXzgRZwPHMk9AxOpHKTHROPcaRzq1T9NH3PoqjNXGKh/s640/Presentation.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Differences between ZIKV BR AB_ES and ZIKV MR766: genes proposed to be involved in viral replication </td></tr>
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<span style="background-color: white; color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">In
conclusion, the infection of hNPC with ZIKV BR AB_ES or ZIKV MR766 induces
apoptosis of hNPC at 72 hrs p.i. probably because of inducing either a G1/S
arrest and/or G2 arrest of the cell cycle although mitotic abnormalities at
least in a subset of infected cells cannot be ruled out.<span style="mso-spacerun: yes;"> </span>These changes in cell cycle progression are
accompanied by a downregulation of genes involved in the onset and progression
of S phase and DNA replication, suggesting that both isolates from the African
and the Asian ZIKV lineage induce either stalled replication forks or prevent
the formation of DNA replication complexes. Indeed, CldU pulse labelling
experiments of ZIKV Mex 1-144 infected foetal (mice) NPC display an extension
of S phase and in ZIKV BR AB_ES infected hNPC the expression of CDKN1A is
upregulated suggesting that the CyclinE-cdk2 complex is inhibited although this
has not been tested using a H1-kinase assay. <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="background-color: white; color: black;">The
downregulation of the expression of several genes involved in the progress of
mitosis in ZIKV MR766 infected hNPC suggests that the infection of hNPC with
ZIKV might also prevent or prolong mitotic exit, promoting aberrant
cytokinesis. </span></span><span style="background-color: white; color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">ZIKV </span><span style="background-color: white; color: #333333; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">FB-GWUH-2016 and ZIKV H/PF/2013 infected hNPC exhibit mother centrioles that lack appendages as well as one to the triplet microtubular blades at the distal ends, potentially resulting in multiple centrosomes during mitosis and consequently in aberrant mitosis. Indeed the hNPC infected with</span><span style="background-color: white;"><span style="color: #333333; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> ZIKV BR/Bahia exhibit abnormal chromosome number (aneuploidy 12 + 17, </span></span><span style="background-color: white;"><span style="color: #333333; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">mono-somy 12/17 and trisomy 12/17) as well as multi- and bipolar cell division followed by formation of micronuclei. </span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg7mFNCAc3uJ0B2A4HNNUDOR8TM6aaih36oyWwEGoCkv3maOMqiW4Mj2URYpbVSPZLbavz7cfwRf_MEk3bwjAg06rFP7DlSCgerOsWrGwTqEgbG2tpX5_J9PqdHvFneQ_CdUdODWgsfoToJ/s1600/Untitled+2.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg7mFNCAc3uJ0B2A4HNNUDOR8TM6aaih36oyWwEGoCkv3maOMqiW4Mj2URYpbVSPZLbavz7cfwRf_MEk3bwjAg06rFP7DlSCgerOsWrGwTqEgbG2tpX5_J9PqdHvFneQ_CdUdODWgsfoToJ/s640/Untitled+2.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure Abnormal centrosomes in ZIKV AS/AM infected hNPC</td></tr>
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<span style="background-color: white; color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span>
<span style="background-color: white; color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">In addition, the downregulation of Centriolin in ZIKV BR AB_ES and
ZIKV MR766 infected hNPC suggests that infected hNPC might either undergo
apoptosis due to arrested cytokinesis or be arrested in G1 phase of the cell
cycle. This supported by findings that both ZIKV </span><span style="background-color: white; color: #333333; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">FB-GWUH-2016
and ZIKV H/PF/2013 infected) but not ZIKV MR766 infected hNPC exhibit impaired neurogenesis due to perturbed centrosomes. </span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="background-color: white; color: #333333;"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="background-color: white; color: #333333;"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="background-color: white; color: #333333;"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="background-color: white; color: #333333;"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="background-color: white; color: #333333;">Similar to </span><span style="background-color: white; color: black;">centrinone treated <span class="apple-converted-space">hTERT</span>-RPE1 immortalized retinal pigment
epithelial cells </span></span><span style="background-color: white; color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">(RPE1 cells), the infection of hNPC with either ZIKV
H/PF/2013, </span><span style="background-color: white; color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">ZIKV </span><span style="background-color: white; color: #333333; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">FB-GWUH-2016 </span><span style="background-color: white; color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">or ZIKV </span><span style="background-color: white; color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">BR
AB</span><span style="background-color: white; color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">_ES might trigger G1 arrest via the induction of 53BP1 in a p53 dependent
manner; interestingly, BRCA-1 has also been implicated in mediating G1/S arrest
as well as Bax dependent apoptosis, suggesting that ZIKV might induce cell
cycle arrest and apoptosis via multiple pathways.</span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="background-color: white; color: black;"><span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span></span><span style="mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"><o:p></o:p></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgAMKxnsfVEgadOVfjZEFP_9vXViHx8siwDc_Xlju-QJjYdAcsl4PrygEEhpEMJUgt-qJ-XyjM-ofs9bnzQ2B5dLcP4OEOApa6wA1fHb98xLqpiylP_5NPbwTxbS8XKTJnjLYPb5XVQaRmo/s1600/Presentation.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgAMKxnsfVEgadOVfjZEFP_9vXViHx8siwDc_Xlju-QJjYdAcsl4PrygEEhpEMJUgt-qJ-XyjM-ofs9bnzQ2B5dLcP4OEOApa6wA1fHb98xLqpiylP_5NPbwTxbS8XKTJnjLYPb5XVQaRmo/s640/Presentation.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Asian and American ZIKV isolates induce cell cycle arrest by different pathways </td></tr>
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<span style="background-color: white; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Different infectious profiles of ZIKV strains were previously described for African (ZIKV ArB41644) and Asian (ZIKV H/PF/2013) infected human iPSc derived neural stem cells (NSC), dermal fibroblast derived hNPC infected with either ZIKV MR766 or ZIKV FSS 13025. So far however, no studies are available that analyse individual viral genes nor extensive studies that examine the progression of the cell cycle in synchronised cells infected with different ZIKV strains. Also, it remains to be seen if primary isolates of African strains are similar to ZIKV MR766 or resemble Asian isolates. Finally, while experiments in hNPC are important, similar experiments are needed in mosquitoe cells.</span><br />
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<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Further reading </span></u></div>
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="35" SemiHidden="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="10" QFormat="true" Name="Title"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="1" SemiHidden="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="11" QFormat="true" Name="Subtitle"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="22" QFormat="true" Name="Strong"/>
<w:LsdException Locked="false" Priority="20" QFormat="true" Name="Emphasis"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="39" Name="Table Grid"/>
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<w:LsdException Locked="false" Priority="60" Name="Light Shading"/>
<w:LsdException Locked="false" Priority="61" Name="Light List"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 1"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 1"/>
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<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 1"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 1"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Revision"/>
<w:LsdException Locked="false" Priority="34" QFormat="true"
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<w:LsdException Locked="false" Priority="29" QFormat="true" Name="Quote"/>
<w:LsdException Locked="false" Priority="30" QFormat="true"
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<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 1"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 1"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 1"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 1"/>
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<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 1"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 1"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 2"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 2"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 2"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 2"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 2"/>
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<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 2"/>
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<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 3"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 3"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 3"/>
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<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 3"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 3"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 4"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 4"/>
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<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 4"/>
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<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 4"/>
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<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 4"/>
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<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 4"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 4"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 5"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 5"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 5"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 5"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 5"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 5"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 5"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 5"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 5"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 5"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 5"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 5"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 5"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 5"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 6"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 6"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 6"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 6"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 6"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 6"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 6"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 6"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 6"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 6"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 6"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 6"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 6"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 6"/>
<w:LsdException Locked="false" Priority="19" QFormat="true"
Name="Subtle Emphasis"/>
<w:LsdException Locked="false" Priority="21" QFormat="true"
Name="Intense Emphasis"/>
<w:LsdException Locked="false" Priority="31" QFormat="true"
Name="Subtle Reference"/>
<w:LsdException Locked="false" Priority="32" QFormat="true"
Name="Intense Reference"/>
<w:LsdException Locked="false" Priority="33" QFormat="true" Name="Book Title"/>
<w:LsdException Locked="false" Priority="37" SemiHidden="true"
UnhideWhenUsed="true" Name="Bibliography"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="TOC Heading"/>
<w:LsdException Locked="false" Priority="41" Name="Plain Table 1"/>
<w:LsdException Locked="false" Priority="42" Name="Plain Table 2"/>
<w:LsdException Locked="false" Priority="43" Name="Plain Table 3"/>
<w:LsdException Locked="false" Priority="44" Name="Plain Table 4"/>
<w:LsdException Locked="false" Priority="45" Name="Plain Table 5"/>
<w:LsdException Locked="false" Priority="40" Name="Grid Table Light"/>
<w:LsdException Locked="false" Priority="46" Name="Grid Table 1 Light"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4"/>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Neuron&rft_id=info%3Apmid%2F27930910&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+Neurobiology+of+Zika+Virus.&rft.issn=0896-6273&rft.date=2016&rft.volume=92&rft.issue=5&rft.spage=949&rft.epage=958&rft.artnum=&rft.au=Li+H&rft.au=Saucedo-Cuevas+L&rft.au=Shresta+S&rft.au=Gleeson+JG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Li H, Saucedo-Cuevas L, Shresta S, & Gleeson JG (2016). The Neurobiology of Zika Virus. <span style="font-style: italic;">Neuron, 92</span> (5), 949-958 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27930910" rev="review">27930910</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27545505&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Neural+Progenitors+in+the+Adult+Mouse+Brain+and+Alters+Proliferation.&rft.issn=1934-5909&rft.date=2016&rft.volume=19&rft.issue=5&rft.spage=593&rft.epage=598&rft.artnum=&rft.au=Li+H&rft.au=Saucedo-Cuevas+L&rft.au=Regla-Nava+JA&rft.au=Chai+G&rft.au=Sheets+N&rft.au=Tang+W&rft.au=Terskikh+AV&rft.au=Shresta+S&rft.au=Gleeson+JG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Li H, Saucedo-Cuevas L, Regla-Nava JA, Chai G, Sheets N, Tang W, Terskikh AV, Shresta S, & Gleeson JG (2016). Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation. <span style="font-style: italic;">Cell stem cell, 19</span> (5), 593-598 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27545505" rev="review">27545505</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Souza BS, Sampaio GL, Pereira CS, Campos GS, Sardi SI, Freitas LA, Figueira CP, Paredes BD, Nonaka CK, Azevedo CM, Rocha VP, Bandeira AC, Mendez-Otero R, Dos Santos RR, & Soares MB (2016). Zika virus infection induces mitosis abnormalities and apoptotic cell death of human neural progenitor cells. Scientific reports, 6 PMID: 28008958</span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+division&rft_id=info%3Apmid%2F20180967&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Distinct+and+redundant+functions+of+cyclin+E1+and+cyclin+E2+in+development+and+cancer.&rft.issn=&rft.date=2010&rft.volume=5&rft.issue=&rft.spage=2&rft.epage=&rft.artnum=&rft.au=Caldon+CE&rft.au=Musgrove+EA&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Caldon CE, & Musgrove EA (2010). Distinct and redundant functions of cyclin E1 and cyclin E2 in development and cancer. <span style="font-style: italic;">Cell division, 5</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20180967" rev="review">20180967</a></span> </span><br />
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+cell+biology&rft_id=info%3Apmid%2F12732615&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=A+novel+human+protein+of+the+maternal+centriole+is+required+for+the+final+stages+of+cytokinesis+and+entry+into+S+phase.&rft.issn=0021-9525&rft.date=2003&rft.volume=161&rft.issue=3&rft.spage=535&rft.epage=45&rft.artnum=&rft.au=Gromley+A&rft.au=Jurczyk+A&rft.au=Sillibourne+J&rft.au=Halilovic+E&rft.au=Mogensen+M&rft.au=Groisman+I&rft.au=Blomberg+M&rft.au=Doxsey+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Gromley A, Jurczyk A, Sillibourne J, Halilovic E, Mogensen M, Groisman I, Blomberg M, & Doxsey S (2003). A novel human protein of the maternal centriole is required for the final stages of cytokinesis and entry into S phase. <span style="font-style: italic;">The Journal of cell biology, 161</span> (3), 535-45 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12732615" rev="review">12732615</a></span><br />
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PloS+one&rft_id=info%3Apmid%2F27367050&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Induction+of+Excess+Centrosomes+in+Neural+Progenitor+Cells+during+the+Development+of+Radiation-Induced+Microcephaly.&rft.issn=&rft.date=2016&rft.volume=11&rft.issue=7&rft.spage=&rft.epage=&rft.artnum=&rft.au=Shimada+M&rft.au=Matsuzaki+F&rft.au=Kato+A&rft.au=Kobayashi+J&rft.au=Matsumoto+T&rft.au=Komatsu+K&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PloS+one&rft_id=info%3Apmid%2F27367050&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Induction+of+Excess+Centrosomes+in+Neural+Progenitor+Cells+during+the+Development+of+Radiation-Induced+Microcephaly.&rft.issn=&rft.date=2016&rft.volume=11&rft.issue=7&rft.spage=&rft.epage=&rft.artnum=&rft.au=Shimada+M&rft.au=Matsuzaki+F&rft.au=Kato+A&rft.au=Kobayashi+J&rft.au=Matsumoto+T&rft.au=Komatsu+K&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Shimada M, Matsuzaki F, Kato A, Kobayashi J, Matsumoto T, & Komatsu K (2016). Induction of Excess Centrosomes in Neural Progenitor Cells during the Development of Radiation-Induced Microcephaly. <span style="font-style: italic;">PloS one, 11</span> (7) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27367050" rev="review">27367050</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+cell+biology&rft_id=info%3Apmid%2F27432897&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=53BP1+and+USP28+mediate+p53+activation+and+G1+arrest+after+centrosome+loss+or+extended+mitotic+duration.&rft.issn=0021-9525&rft.date=2016&rft.volume=214&rft.issue=2&rft.spage=155&rft.epage=66&rft.artnum=&rft.au=Meitinger+F&rft.au=Anzola+JV&rft.au=Kaulich+M&rft.au=Richardson+A&rft.au=Stender+JD&rft.au=Benner+C&rft.au=Glass+CK&rft.au=Dowdy+SF&rft.au=Desai+A&rft.au=Shiau+AK&rft.au=Oegema+K&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Meitinger F, Anzola JV, Kaulich M, Richardson A, Stender JD, Benner C, Glass CK, Dowdy SF, Desai A, Shiau AK, & Oegema K (2016). 53BP1 and USP28 mediate p53 activation and G1 arrest after centrosome loss or extended mitotic duration. <span style="font-style: italic;">The Journal of cell biology, 214</span> (2), 155-66 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27432897" rev="review">27432897</a></span> </span><br />
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Oncotarget&rft_id=info%3Apmid%2F26623723&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Aberrant+modulation+of+the+BRCA1+and+G1%2FS+cell+cycle+pathways+in+alcoholic+hepatitis+patients+with+Mallory+Denk+Bodies+revealed+by+RNA+sequencing.&rft.issn=&rft.date=2015&rft.volume=6&rft.issue=40&rft.spage=42491&rft.epage=503&rft.artnum=&rft.au=Liu+H&rft.au=Gong+M&rft.au=French+BA&rft.au=Liao+G&rft.au=Li+J&rft.au=Tillman+B&rft.au=French+SW&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Liu H, Gong M, French BA, Liao G, Li J, Tillman B, & French SW (2015). Aberrant modulation of the BRCA1 and G1/S cell cycle pathways in alcoholic hepatitis patients with Mallory Denk Bodies revealed by RNA sequencing. <span style="font-style: italic;">Oncotarget, 6</span> (40), 42491-503 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26623723" rev="review">26623723</a></span> <br />
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F28008958&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus+infection+induces+mitosis+abnormalities+and+apoptotic+cell+death+of+human+neural+progenitor+cells.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=39775&rft.epage=&rft.artnum=&rft.au=Souza+BS&rft.au=Sampaio+GL&rft.au=Pereira+CS&rft.au=Campos+GS&rft.au=Sardi+SI&rft.au=Freitas+LA&rft.au=Figueira+CP&rft.au=Paredes+BD&rft.au=Nonaka+CK&rft.au=Azevedo+CM&rft.au=Rocha+VP&rft.au=Bandeira+AC&rft.au=Mendez-Otero+R&rft.au=Dos+Santos+RR&rft.au=Soares+MB&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"></span>thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com12tag:blogger.com,1999:blog-8715161762555608131.post-83916289307229841442017-01-17T18:02:00.000-05:002017-01-18T11:23:17.788-05:00Axl and GAS6: apoptotic mimicry and NLRP-3 inhibition during Zika Virus infection <div style="text-align: justify;">
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">Zika Virus (ZIKV) is a
positive sense RNA virus that belongs to the Flavivirus genus of the<i> Flaviviridae</i> family that includes other
human pathogens including Hepatitis C Virus (HCV), Yellow Fever Virus (YFV),
West Nile Virus, Dengue Virus (DENV), Tick Borne Encephalitis Virus (TBEV), and
Japanese Encephalitis Virus (JEV). <o:p></o:p></span></span></div>
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<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">Although being first
isolated in 1947, until recently ZIKV was not associated with severe disease;
following the introduction of ZIKV in the Americas however, foetal ZIKV
infection became associated with neonatal cognitive defects, including viral
Microcephaly as well as GBS in adult patients. <o:p></o:p></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">Like other flaviviruses
such as DENV or JEV, ZIKV entry into host cells is mediated by several cell
surface receptors that belong to the Tyro3-Axl-Mer (TAM) family of receptor
tyrosine kinases, T cell immunoglobulin and mucin domain (TIM) phosphatidylserine
(PS) and C-type lectin receptor families followed by endocytosis of the viral
particle. As discussed below, activation of at least one of these receptors,
Axl, by ZIKV might promote the inhibition of the secretion of pro-inflammatory
cytokines. <o:p></o:p></span></span></div>
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<b style="mso-bidi-font-weight: normal;"><span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">Chloroquine:
targeting multiple steps of viral infection? <o:p></o:p></span></span></b></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">To investigate if the
degradation of viral and/or cellular proteins within the lysosome impacts the
replication of ZIKV MR766, ZIKV PE/243 or ZIKV Recife, infected Vero cells were
treated for 5 days or for 48 hrs with varying concentrations of Chloroquine
(CQ) and viral replication was assessed by flow cytometry and indirect
immunofluorescence analysis for the presence of the viral E protein as well as
measuring viral titres. Results obtained from flow cytometry analysis of Vero
cells infected either with ZIKV MR766 or ZIKV Recife 5 days p.i. and treated
with 25 μM CQ exhibit a reduction of viral replication by 65% (ZIKV MR766) or
70% (ZIKV Recife) respectively concomitant with a decrease in viral titres and
an increase in cell viability. In a similar way, treatment of ZIKV MR766
infected human brain microvascular endothelial cells (hBMEC), that serve as a
model for the (human) blood –brain barrier, with up to 50 μM CQ reduces viral
replication up to 45% whilst increasing cell viability. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">As discussed before, the
infection of human neural progenitor cells (hNPC) with ZIKV MR766, the
infection of human neuroepithelial stem cells (NES) with ZIKV FSS13025 or the
infection of foetal human neural progenitor cells with ZIKV PRV ABC59 or the infection
of iPSC-derived human neural stem cells (NSC) or human astrocytes with ZIKV
ArB41644 induces extensive Caspase-3 dependent apoptosis of infected cells.
Similar to results obtained from Vero cells or hBMEC, ZIKV MR766 infected human
NSC derived from human fibroblast cells are protected from ZIKV induced
apoptosis upon treatment with CQ in addition to reduced viral replication.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">CQ mediated inhibition of
viral replication can occur at various stages during the viral replication,
either by inhibiting viral entry, release of the viral genome into the
cytoplasm or at later stages of the viral replication such as inhibiting the
degradation of PRR or STAT2, the degradation of TLR3 by viral induced autophagy
or lipophagy. </span></span><br />
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgcfZ7zanACfXYkF9q31_ndlrDln4XuD-xPLvHCju15Y4MdvrTwHuI8c941kbZtrbSuaSkSjT5HjZBQKjr_QOCtCJCq3epR0SMhl4LY89Lx3qabjYpU4kgUALkLqco5GwrQ3Sm31QVBDbo0/s1600/ZIKV+Axl+CQ+blog.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgcfZ7zanACfXYkF9q31_ndlrDln4XuD-xPLvHCju15Y4MdvrTwHuI8c941kbZtrbSuaSkSjT5HjZBQKjr_QOCtCJCq3epR0SMhl4LY89Lx3qabjYpU4kgUALkLqco5GwrQ3Sm31QVBDbo0/s640/ZIKV+Axl+CQ+blog.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Chloroquine treatment inhibition of lipophagy</td></tr>
</tbody></table>
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">In addition, treatment of infected cells with CQ might also
prevent the degradation of IFTIM-2 and IFTIM-3 positive endosomes that also
contain the viral capsid or preventing the degradation of TLR-3 by autophagy following binding of viral RNA and thus promoting the induction of antiviral signalling. Indeed, the application of CQ from 30 min to 12 hrs
p.i. decreases viral titres, indicating that several steps of the viral
replication are sensitive to CQ treatment with viral entry being mostly
affected. <o:p></o:p></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<br /></div>
<div class="MsoNormal">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGBZdDfkzBBmuK5HQpdT0EzBiferQ0k8xXbwyWnF4a3KDjW90-q8d_wMp3yezT269rFSrVNmlyTBCSEb8ohMovxAYDvVuKTFSFFlPtyfAl-h4GoizW2CysG0BPN-Rodhbj6rx9upy8Qn6b/s1600/ZIKV+Axl+CQ+blog.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGBZdDfkzBBmuK5HQpdT0EzBiferQ0k8xXbwyWnF4a3KDjW90-q8d_wMp3yezT269rFSrVNmlyTBCSEb8ohMovxAYDvVuKTFSFFlPtyfAl-h4GoizW2CysG0BPN-Rodhbj6rx9upy8Qn6b/s640/ZIKV+Axl+CQ+blog.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Chloroquine treatment and TLR-3 signalling </td></tr>
</tbody></table>
<br /></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span lang="EN-US" style="color: red;"><br />
</span><b style="mso-bidi-font-weight: normal;"><span lang="EN-US" style="color: black;">Axl and ZIKV entry: viral apoptotic mimicry </span></b><span lang="EN-US" style="color: red;"><o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">Flavivirus entry into
susceptible cells is mediated by several receptors including Axl receptor
tyrosine kinase which belongs to the TAM family, a group of tyrosine kinase
receptors that are involved in the clearance of apoptotic cells by recognizing
and binding to Phosphatidylserine (PS) which is located on the cell surface of
apoptotic cells, a process which has been previously discussed for Ebola Virus.
In general, the binding of viral particles that contain PS is mediated by
bridging molecules such as Gas6 followed by clathrin mediated entry of viral
particles by endocytosis and subsequent formation of early endosomes and
subsequent release of the viral genome. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">In the case of HCV, DENV,
YFV and WNV the ectopic expression of either TIM and/or TAM receptors not only
enhances viral replication but PS is also incorporated into the membrane of
DENV particles, suggesting that apoptotic mimicry is being used for the
infection of TAM and TIM expressing cells by members of the <i style="mso-bidi-font-style: normal;">Flaviviridae</i> in a Gas6 and ProteinS
(PROS) dependent manner.<o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">In the case of cells that
support the replication of ZIKV, the expression of known Flavivirus entry
factors including Axl is necessary to support viral replication; indeed, the
expression of siRNA targeting Axl or the pretreatment of with Axl neutralizing
antibodies of dermal reduces the replication of ZIKV MR766 in primary human
dermal fibroblast cells. Accordingly, hNPC, hNSC, human astrocytes, human
microglial cells and human radial glial cells of the developing neocortex express
high levels of Axl mRNA whereas the expression of Axl mRNA in human placental
cells varies with gestational age, correlating with the ability to support ZIKV
replication. Like placental cells, microglial cells of the ventricular zone
(VZ) and subventricular zone (SVZ) -GFAP+ cells such as radial glial progenitor
cells at the ventricular border- derived from a foetus at 20 gestational weeks
(GW) express high levels of Axl as indicated by indirect immunofluorescence
staining whereas at 26 GW, Axl can only be detected in residual GFAP+ cells,
thus explaining the absence of ZIKV E protein in mature neuronal cells. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">Experimentally, the
infection of an immortalized microglial cell line (CHME-3) as well as human and
murine astrocytes but not hNPC with ZIKV HD78788 (an African isolate) can be
inhibited both a polyclonal antibody against Axl as well as by MYD1 (an Axl
decoy receptor) that sequesters Gas6, indicating that the entry of ZIKV HD78788
is dependent on both Axl and Gas6, suggesting that ZIKV is (at least in part)
dependent on Axl and Gas6, utilizing viral apoptotic mimicry similar to DENV.
Accordingly, the infection of induced pluripotent stem cell (iPSC) derived NPC
and cerebral organoids with ZIKV PRVABC59 is not dependent on the presence of
Axl since genetic ablation of Axl using CRISPR does not prevent ZIKV
replication and ZIKV induced and Caspase-3 dependent apoptosis nor ZIKV
dependent decrease of cell proliferation, whereas the replication and entry of
both ZIKV H/PF/2013 and ZIKV HD78788 is abrogated in CHME-3 Axl<sup>-/- </sup>cells.
<o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">As mentioned above,
Flavivirus entry is dependent on clathrin mediated endocytosis. Consequently,
the downregulation of either clathrin heavy chain (CLTC) or dynamin-2 (DNM-2)
by transfecting siCLTC or siDNM-2 into CHME-3 cells and Hela-Axl cells impairs
ZIKV HD78788 replication. Further analysis using GFP-tagged Rab5GTPase and
Rab7GTPase WT and dominant negative (DN) constructs suggest that viral
particles are targeted to the early endosome (EEA) since the expression of
Rab5GTPase DN and Rab7GTPase WT but not Rab7GTPase DN reduces ZIKV HD78788
replication. In this scenario, the expression of a dominate negative mutant of
Rab5 prevents the formation of the EEA whereas the expression of Rab7 WT
promotes the formation of late endosomes and subsequent degradation of viral
particles in the lysosomes. </span></span><br />
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjt2ug4-V2ho6v2gWIdNlM-xzBYS7iLO-L02He8CpFRV2k5gy1uNi_NbgmBF81dFf7l9gT6RJED0Lzdzmk6S1_d2Z33eGmABNsfYkWdh_PCkTXQXhV6ZXpfXD2EKxU4daSGYIjaNJA2XWAW/s1600/ZIKV+Axl+CQ+blog.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjt2ug4-V2ho6v2gWIdNlM-xzBYS7iLO-L02He8CpFRV2k5gy1uNi_NbgmBF81dFf7l9gT6RJED0Lzdzmk6S1_d2Z33eGmABNsfYkWdh_PCkTXQXhV6ZXpfXD2EKxU4daSGYIjaNJA2XWAW/s640/ZIKV+Axl+CQ+blog.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Rab5GTPase DN and Endosome formation: inhibition ? </td></tr>
</tbody></table>
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;">Furthermore, Rab5GTPase DN might also prevent the
formation viral replication complexes, whereas the overexpression of Rab7GTPase WT
might inhibit viral replication by promoting the formation of autolysosomes. So
far it is not clear if the expression of Rab5GTPase DN stabilizes IFITM-2 and/or
IFTIM-3 and thus contributes to IFITM-3 dependent inhibition of the fusion of
the viral membrane and instead promotes the degradation of the viral content as
it is the case for Influenza A. Also, so far it is not clear if the release of
the ZIKV genome is dependent on the formation of the late endosome as it is the
case for YFV and JEV.</span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjDw34I_FRVDYkZdly96Plmf1SFGvaRelucvXofUtyrtat6qjUtGAoBDHdofzv9fXkdpcixMM7f8pFgQuRZn4HMC5pzXuEzz2NJtLk9f_bEFFJn8q0XYwxyvwvIVrHXAhZg92A19L4PMqCr/s1600/ZIKV+Axl+CQ+blog.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjDw34I_FRVDYkZdly96Plmf1SFGvaRelucvXofUtyrtat6qjUtGAoBDHdofzv9fXkdpcixMM7f8pFgQuRZn4HMC5pzXuEzz2NJtLk9f_bEFFJn8q0XYwxyvwvIVrHXAhZg92A19L4PMqCr/s640/ZIKV+Axl+CQ+blog.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Rab5GTPase DN and Rab7GTPase WT: IFITM-2/-3 stabilization ? </td></tr>
</tbody></table>
<br /></div>
<div class="MsoNormal">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><b style="mso-bidi-font-weight: normal;"><span lang="EN-US">Axl
and the immune response: role of Gas6 in NLRP-3 inflammasome inhibition </span></b><span lang="EN-US"><o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">The interaction of Gas6
with Axl and other members of the TAM family of receptor tyrosine kinases has
been shown to lead to severe hepatic injury in Gas6 <sup>-/- </sup>mice upon
the induction of liver injury by treating Gas6 <sup>-/- </sup>mice with CCl<sub>4</sub>.
<o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">Recently published results
showed that in murine P388D1 macrophages, Axl undergoes autophosphorylation of
two Tyr residues (Tyr815 and Tyr 860) within the cytoplasmic domain upon
treatment with GAS6 for 24 hrs. The autophosphorylation of Axl is followed <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">by an increase in LC3-II
positive autophagic vesicles and increased autophagic flux which is accompanied
by the induction of Atg5, Beclin-1 and LC3 expression. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">GAS6/Axl induced
autophagy however is not induced by the mTOR pathway since the neither the
treatment of PD3881 cells with Rapamycin nor starvation inhibits the formation
of autophagosomes by Axl; in contrast, treatment of PD3881 cells with SB203580
(MAPK 11/14 inhibitor) as well as the transfection with shMAPK14 abolishes the
formation of autophagosomes, indicating that autophagy induced by GAS6/Axl is
indeed induced by MAPK 14 mediated formation of autophagosomes. <o:p></o:p></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span lang="EN-US">Autophagy is involved in
several biological processed such as the clearance of organelles and misfolded
proteins. Recent observations suggest that autophagy is also involved in the
maturation of the NLRP-3 inflammasome, which because of being induced in a
two-step process first by a </span><span style="background-color: white; color: black;">Toll-like receptor
(TLR)/nuclear factor (NF)-κB pathway that induces the expression of NLRP-3 and
then by PAMPs and DAMPs which induces the assembly of a multi-protein complex
that consists of the linker protein ASC that binds both pro-Caspase-1 via the
CARD domain and NLRP. Subsequent activation of Caspase-1 cleaves pro-IL-1β into
the mature form of IL-1β. </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="background-color: white; color: black;"><br /></span></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhEE1hvDRrBVzTmtkp8W7QLQGmuoHzAknYIs1nvT3kaaEEQ_bxCHPRkZxyCzONSVJUEw5j-8hmnbNLeiGfjdZk2t9pF4FcewC73dywDG7K3pbwXolLyEIRNhaqDco53vRI-Wkh8HeTy5VA9/s1600/ZIKV+Axl+CQ+blog.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhEE1hvDRrBVzTmtkp8W7QLQGmuoHzAknYIs1nvT3kaaEEQ_bxCHPRkZxyCzONSVJUEw5j-8hmnbNLeiGfjdZk2t9pF4FcewC73dywDG7K3pbwXolLyEIRNhaqDco53vRI-Wkh8HeTy5VA9/s640/ZIKV+Axl+CQ+blog.006.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Formation of the NLRP-3 Inflammasome</td></tr>
</tbody></table>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="background-color: white; color: black;"><br /></span></span>
<span style="background-color: white; font-family: "trebuchet ms" , sans-serif;">Upon treatment with GAS6, Axl </span><sup style="background-color: white; font-family: 'Trebuchet MS', sans-serif;">+/+</sup><span style="background-color: white; font-family: "trebuchet ms" , sans-serif;">
macrophages exhibit decreased levels of cleaved (mature) IL-1β, suggesting that
the activation of Axl inhibits NLRP-3 mediated activation of Caspase-1 similar
to glibenclamide treatment. Most importantly however, the treatment of
autophagy deficient Atg7 </span><sup style="background-color: white; font-family: 'Trebuchet MS', sans-serif;">fl/fl</sup><span style="background-color: white; font-family: "trebuchet ms" , sans-serif;"> conditional knockout macrophages with
GAS6 does not prevent the maturation of IL-1β, indicating that Axl induced
autophagy inhibits the NLRP-3 inflammasome.</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="background-color: white; font-family: "trebuchet ms" , sans-serif;">In
the context of viral infections, GAS6 coated HIV-1 and WNV not only bind to and
activate Axl but also inhibits the Type-I Interferon response, suggesting that
GAS6 not only facilitates viral entry but also inhibits antiviral signalling.</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="background-color: white; color: black;">In
the case of ZIKV HD78788 infected CHME-3 wt cells treated with R428 –an Axl
inhibitor- or the infected CHME-3 Axl KO cells, infection not only </span><span lang="EN-US">increases
Interferon-β and SOCS-1 mRNA levels but also in increased expression of TNF-α,
IL-6, and IL-1β, suggesting that the binding of ZIKV particles to GAS6 and Axl
does induce the inhibition of NLRP-3. If this inhibition however is mediated by
the induction of autophagy has not been demonstrated yet.<o:p></o:p></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span>
<br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEivl2-sp6kosOSua8ch3W7wZLBb7nljJa2gJhTRiHjGxiNQib3ncmb6BP40Ls_f_fZK7TUWjl-N9KrmTo7E0zaOrqVG2P1JColkLQQrROuf0Lj-9J3_DYfKZSq1VFjaVPDw86JjlxYvoOV3/s1600/ZIKV+Axl+CQ+blog.007.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEivl2-sp6kosOSua8ch3W7wZLBb7nljJa2gJhTRiHjGxiNQib3ncmb6BP40Ls_f_fZK7TUWjl-N9KrmTo7E0zaOrqVG2P1JColkLQQrROuf0Lj-9J3_DYfKZSq1VFjaVPDw86JjlxYvoOV3/s640/ZIKV+Axl+CQ+blog.007.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: GAS6/Axl and ZIKV: inducing degradation of NLRP-3 via autophagy and inhibition of TLR-3 mediated signalling pathways ? </td></tr>
</tbody></table>
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
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<span lang="EN-US"><span style="font-family: "trebuchet ms" , sans-serif;">In conclusion, the
treatment of susceptible cells with Chloroquine might inhibit ZIKV infection at
various stages of viral entry. One possibility is the stabilization of IFTIM-2
and -3 by preventing lysosomal degradation. Another possibility is that
Chloroquine stabilizes the NLRP-3 inflammasome and thus increases the expression
of cytokines by preventing the degradation of NLRP-3. Further studies are
however needed to determine the role of NLRP-3 inhibition and IFITM-2/-3 during
ZIKV infection of susceptible foetal cells and abnormal foetal
development.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif;">Apart from Axl, ZIKV uptake
might also be mediated by other receptors, including TIM and Tyro-3. The
presence of a co-receptor therefore might allow not only ZIKV entry but also
the induction of TLR mediated activation of NLRP-3. Axl induced formation of
autophagosomes therefore might prevent the activation of NLRP-3 by TLR and thus
prevent the recruitment of Caspase-1 to (inactive) NLRP-3 monomers. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
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<span lang="EN-US" style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">The expression of
Rab5GTPase DN therefore might not only stabilize IFTIM-2 and -3 but also
prevent the induction of autophagy following the binding of the GAS6/ZIKV
complex to Axl without affecting viral entry (unless it is dependent on
Rab5GTPase). Viral RNA recognized by PAMPs induces the NLRP-3 in cells
expressing Rab5GTPase DN and thus the secretion of pro-inflammatory cytokines. Further
experiments are however needed to validate this hypothesis. </span><span style="font-family: "helvetica";"><o:p></o:p></span></span></div>
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Message Header"/>
<w:LsdException Locked="false" Priority="11" QFormat="true" Name="Subtitle"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Salutation"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Date"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Heading"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Block Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Hyperlink"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="FollowedHyperlink"/>
<w:LsdException Locked="false" Priority="22" QFormat="true" Name="Strong"/>
<w:LsdException Locked="false" Priority="20" QFormat="true" Name="Emphasis"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Document Map"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Plain Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="E-mail Signature"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Top of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Bottom of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal (Web)"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Acronym"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Address"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Cite"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Code"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Definition"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Keyboard"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Preformatted"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Sample"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Typewriter"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Variable"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal Table"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="annotation subject"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="No List"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Contemporary"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Elegant"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Professional"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Balloon Text"/>
<w:LsdException Locked="false" Priority="39" Name="Table Grid"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Theme"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 9"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Placeholder Text"/>
<w:LsdException Locked="false" Priority="1" QFormat="true" Name="No Spacing"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading"/>
<w:LsdException Locked="false" Priority="61" Name="Light List"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 1"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 1"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 1"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 1"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 1"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Revision"/>
<w:LsdException Locked="false" Priority="34" QFormat="true"
Name="List Paragraph"/>
<w:LsdException Locked="false" Priority="29" QFormat="true" Name="Quote"/>
<w:LsdException Locked="false" Priority="30" QFormat="true"
Name="Intense Quote"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 1"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 1"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 1"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 1"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 1"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 1"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 1"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 2"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 2"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 2"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 2"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 2"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 2"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 2"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 2"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 2"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 2"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 2"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 3"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 3"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 3"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 3"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 3"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 3"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 3"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 3"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 3"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 3"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 3"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 3"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 3"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 4"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 4"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 4"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 4"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 4"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 4"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 4"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 4"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 4"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 4"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 4"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 4"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 4"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 4"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 5"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 5"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 5"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 5"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 5"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 5"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 5"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 5"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 5"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 5"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 5"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 5"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 5"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 5"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 6"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 6"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 6"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 6"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 6"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 6"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 6"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 6"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 6"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 6"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 6"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 6"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 6"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 6"/>
<w:LsdException Locked="false" Priority="19" QFormat="true"
Name="Subtle Emphasis"/>
<w:LsdException Locked="false" Priority="21" QFormat="true"
Name="Intense Emphasis"/>
<w:LsdException Locked="false" Priority="31" QFormat="true"
Name="Subtle Reference"/>
<w:LsdException Locked="false" Priority="32" QFormat="true"
Name="Intense Reference"/>
<w:LsdException Locked="false" Priority="33" QFormat="true" Name="Book Title"/>
<w:LsdException Locked="false" Priority="37" SemiHidden="true"
UnhideWhenUsed="true" Name="Bibliography"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="TOC Heading"/>
<w:LsdException Locked="false" Priority="41" Name="Plain Table 1"/>
<w:LsdException Locked="false" Priority="42" Name="Plain Table 2"/>
<w:LsdException Locked="false" Priority="43" Name="Plain Table 3"/>
<w:LsdException Locked="false" Priority="44" Name="Plain Table 4"/>
<w:LsdException Locked="false" Priority="45" Name="Plain Table 5"/>
<w:LsdException Locked="false" Priority="40" Name="Grid Table Light"/>
<w:LsdException Locked="false" Priority="46" Name="Grid Table 1 Light"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark"/>
<w:LsdException Locked="false" Priority="51" Name="Grid Table 6 Colorful"/>
<w:LsdException Locked="false" Priority="52" Name="Grid Table 7 Colorful"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 1"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 1"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 1"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 1"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 1"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 2"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 2"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 2"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 2"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 3"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 3"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 3"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 3"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 4"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 4"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 4"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 4"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 4"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 4"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 4"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 5"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 5"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 5"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 5"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 5"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 5"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 5"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 6"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 6"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 6"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 6"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 6"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 6"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 6"/>
<w:LsdException Locked="false" Priority="46" Name="List Table 1 Light"/>
<w:LsdException Locked="false" Priority="47" Name="List Table 2"/>
<w:LsdException Locked="false" Priority="48" Name="List Table 3"/>
<w:LsdException Locked="false" Priority="49" Name="List Table 4"/>
<w:LsdException Locked="false" Priority="50" Name="List Table 5 Dark"/>
<w:LsdException Locked="false" Priority="51" Name="List Table 6 Colorful"/>
<w:LsdException Locked="false" Priority="52" Name="List Table 7 Colorful"/>
<w:LsdException Locked="false" Priority="46"
Name="List Table 1 Light Accent 1"/>
<w:LsdException Locked="false" Priority="47" Name="List Table 2 Accent 1"/>
<w:LsdException Locked="false" Priority="48" Name="List Table 3 Accent 1"/>
<w:LsdException Locked="false" Priority="49" Name="List Table 4 Accent 1"/>
<w:LsdException Locked="false" Priority="50" Name="List Table 5 Dark Accent 1"/>
<w:LsdException Locked="false" Priority="51"
Name="List Table 6 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="52"
Name="List Table 7 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="46"
Name="List Table 1 Light Accent 2"/>
<w:LsdException Locked="false" Priority="47" Name="List Table 2 Accent 2"/>
<w:LsdException Locked="false" Priority="48" Name="List Table 3 Accent 2"/>
<w:LsdException Locked="false" Priority="49" Name="List Table 4 Accent 2"/>
<w:LsdException Locked="false" Priority="50" Name="List Table 5 Dark Accent 2"/>
<w:LsdException Locked="false" Priority="51"
Name="List Table 6 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="52"
Name="List Table 7 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="46"
Name="List Table 1 Light Accent 3"/>
<w:LsdException Locked="false" Priority="47" Name="List Table 2 Accent 3"/>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgx7KExa5tWFhR5QWMhzxzc3deVzo53EmRL4u7zLiim9lUIRmf2W4Mib7vCQwP03SrhWMGqrSgr3lYEuMzkBi5dQ9Bu4o3_HFZmadNb34RVZeGPtXYxR2HbD9YvzQszloSEP-iwzjej2_09/s1600/ZIKV+Axl+CQ+blog.005.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgx7KExa5tWFhR5QWMhzxzc3deVzo53EmRL4u7zLiim9lUIRmf2W4Mib7vCQwP03SrhWMGqrSgr3lYEuMzkBi5dQ9Bu4o3_HFZmadNb34RVZeGPtXYxR2HbD9YvzQszloSEP-iwzjej2_09/s640/ZIKV+Axl+CQ+blog.005.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Inhibition of viral entry and Axl mediated induction of autophagy by Rab5GTPase DN ? </td></tr>
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<span style="font-family: "trebuchet ms", sans-serif;">A screen for inhibitors of ZIKV infection of U20S, human brain microvascular cells (HBMC) and human placental trophoblast cells (JEG-3) with ZIKV MR766, ZIKV Mex2-81 or ZIKV FSS13025 lead to the identification of 19 (U2OS), 12 (HBMC) and 16 (JEG-3) compounds that inhibit ZIKV replication, with Nanchangmycin the most potent inhibitor in all cell types (in addition to Vero cells) bar HBMC tested. Cells infected with ZIKV and treated for 4 hrs with Nanchangmycin exhibit decreased viral replication as determined by indirect immunofluorescence for the viral E protein at 24 hrs p.i. In a similar way, the inhibition of Axl by treating infected cells with Cabozantinib during the first 4 hrs following ZIKV infection decreases viral replication as well, indicating that the RTK activity of Axl is indeed necessary for viral entry. </span><br />
<span style="font-family: "trebuchet ms", sans-serif;"><br /></span>
<span style="font-family: "trebuchet ms", sans-serif;">A fluorescence based uptake assay determined that both Nanchangmycin and Cabozantinib block the uptake of viral particles rather than inhibiting processes such as the induction of autophagy or the formation of EEA. In this assay, Nanchangmycin or Cabozantinib pre-treated U2OS cells were infected with ZIKV Mex2-81 in the presence of either drug at 4°C to synchronise the infection and then released for 3 hrs at 37°C to allow the entry of viral uptake prior to removal of the medium containing the drug and treating the infected cells with NH4Cl to prevent further viral uptake. Like U2O2 cells, both Cabozantinib and Nanchangmycin also block the entry of ZIKV FSS13025 into human primary uterine microvascular endothelial cells (UtMEC), HUVEC as well as primary placental fibroblast cells; in addition, Nanchangmycin also inhibits viral uptake of ZIKV Mex2-81 into a mixed population of murine neurons.</span><br />
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<span style="font-family: "trebuchet ms", sans-serif;"></span><br />
<span style="font-family: "trebuchet ms", sans-serif;">Furthermore, both Nanchangmycin and Cabozantinib also inhibit the entry of other viruses, including DENV, WNV, and CHIKV, that use clathrin mediated endocytosis to enter cells. </span><br />
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Name="footer"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index heading"/>
<w:LsdException Locked="false" Priority="35" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="caption"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="table of figures"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="envelope address"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="envelope return"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="footnote reference"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="annotation reference"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="line number"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="page number"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="endnote reference"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="endnote text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="table of authorities"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="macro"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="toa heading"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 5"/>
<w:LsdException Locked="false" Priority="10" QFormat="true" Name="Title"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Closing"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Signature"/>
<w:LsdException Locked="false" Priority="1" SemiHidden="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Message Header"/>
<w:LsdException Locked="false" Priority="11" QFormat="true" Name="Subtitle"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Salutation"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Date"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Heading"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Block Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Hyperlink"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="FollowedHyperlink"/>
<w:LsdException Locked="false" Priority="22" QFormat="true" Name="Strong"/>
<w:LsdException Locked="false" Priority="20" QFormat="true" Name="Emphasis"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Plain Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="E-mail Signature"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Top of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Bottom of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal (Web)"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Acronym"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Address"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Cite"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Code"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Definition"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Keyboard"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Preformatted"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Sample"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Typewriter"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Variable"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal Table"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="annotation subject"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="No List"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Contemporary"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Elegant"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Professional"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Balloon Text"/>
<w:LsdException Locked="false" Priority="39" Name="Table Grid"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 9"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Placeholder Text"/>
<w:LsdException Locked="false" Priority="1" QFormat="true" Name="No Spacing"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading"/>
<w:LsdException Locked="false" Priority="61" Name="Light List"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 1"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 1"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 1"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 1"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 1"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Revision"/>
<w:LsdException Locked="false" Priority="34" QFormat="true"
Name="List Paragraph"/>
<w:LsdException Locked="false" Priority="29" QFormat="true" Name="Quote"/>
<w:LsdException Locked="false" Priority="30" QFormat="true"
Name="Intense Quote"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 1"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 1"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 1"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 1"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 1"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 1"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 1"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 2"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 2"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 2"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 2"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 2"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 2"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 2"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 2"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 2"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 2"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 2"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 3"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 3"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 3"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 3"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 3"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 3"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 3"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 3"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 3"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 3"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 3"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 3"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 3"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 4"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 4"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 4"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 4"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 4"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 4"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 4"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 4"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 4"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 4"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 4"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 4"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 4"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 4"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 5"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 5"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 5"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 5"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 5"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 5"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 5"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 5"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 5"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 5"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 5"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 5"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 5"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 5"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 6"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 6"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 6"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 6"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 6"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 6"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 6"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 6"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 6"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 6"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 6"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 6"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 6"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 6"/>
<w:LsdException Locked="false" Priority="19" QFormat="true"
Name="Subtle Emphasis"/>
<w:LsdException Locked="false" Priority="21" QFormat="true"
Name="Intense Emphasis"/>
<w:LsdException Locked="false" Priority="31" QFormat="true"
Name="Subtle Reference"/>
<w:LsdException Locked="false" Priority="32" QFormat="true"
Name="Intense Reference"/>
<w:LsdException Locked="false" Priority="33" QFormat="true" Name="Book Title"/>
<w:LsdException Locked="false" Priority="37" SemiHidden="true"
UnhideWhenUsed="true" Name="Bibliography"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="TOC Heading"/>
<w:LsdException Locked="false" Priority="41" Name="Plain Table 1"/>
<w:LsdException Locked="false" Priority="42" Name="Plain Table 2"/>
<w:LsdException Locked="false" Priority="43" Name="Plain Table 3"/>
<w:LsdException Locked="false" Priority="44" Name="Plain Table 4"/>
<w:LsdException Locked="false" Priority="45" Name="Plain Table 5"/>
<w:LsdException Locked="false" Priority="40" Name="Grid Table Light"/>
<w:LsdException Locked="false" Priority="46" Name="Grid Table 1 Light"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark"/>
<w:LsdException Locked="false" Priority="51" Name="Grid Table 6 Colorful"/>
<w:LsdException Locked="false" Priority="52" Name="Grid Table 7 Colorful"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 1"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 1"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 1"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 1"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 1"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 2"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 2"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 2"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 2"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 3"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 3"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 3"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 3"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 3"/>
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<span style="font-family: "trebuchet ms" , sans-serif;"><u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><br /></span></u>
<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;">Further reading</span></u></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;">Li H, Saucedo-Cuevas L, Shresta S, & Gleeson JG (2016). The Neurobiology of Zika Virus. <span style="font-style: italic;">Neuron, 92</span> (5), 949-958 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27930910" rev="review">27930910</a></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif;">Tabata T, Petitt M, Puerta-Guardo H, Michlmayr D, Wang C, Fang-Hoover J, Harris E, & Pereira L (2016). Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission. <span style="font-style: italic;">Cell host & microbe, 20</span> (2), 155-66 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27443522" rev="review">27443522</a></span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America&rft_id=info%3Apmid%2F27911847&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus+cell+tropism+in+the+developing+human+brain+and+inhibition+by+azithromycin.&rft.issn=0027-8424&rft.date=2016&rft.volume=113&rft.issue=50&rft.spage=14408&rft.epage=14413&rft.artnum=&rft.au=Retallack+H&rft.au=Di+Lullo+E&rft.au=Arias+C&rft.au=Knopp+KA&rft.au=Laurie+MT&rft.au=Sandoval-Espinosa+C&rft.au=Mancia+Leon+WR&rft.au=Krencik+R&rft.au=Ullian+EM&rft.au=Spatazza+J&rft.au=Pollen+AA&rft.au=Mandel-Brehm+C&rft.au=Nowakowski+TJ&rft.au=Kriegstein+AR&rft.au=DeRisi+JL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
<div style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif; font-size: small;">
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America&rft_id=info%3Apmid%2F27911847&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus+cell+tropism+in+the+developing+human+brain+and+inhibition+by+azithromycin.&rft.issn=0027-8424&rft.date=2016&rft.volume=113&rft.issue=50&rft.spage=14408&rft.epage=14413&rft.artnum=&rft.au=Retallack+H&rft.au=Di+Lullo+E&rft.au=Arias+C&rft.au=Knopp+KA&rft.au=Laurie+MT&rft.au=Sandoval-Espinosa+C&rft.au=Mancia+Leon+WR&rft.au=Krencik+R&rft.au=Ullian+EM&rft.au=Spatazza+J&rft.au=Pollen+AA&rft.au=Mandel-Brehm+C&rft.au=Nowakowski+TJ&rft.au=Kriegstein+AR&rft.au=DeRisi+JL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Retallack H, Di Lullo E, Arias C, Knopp KA, Laurie MT, Sandoval-Espinosa C, Mancia Leon WR, Krencik R, Ullian EM, Spatazza J, Pollen AA, Mandel-Brehm C, Nowakowski TJ, Kriegstein AR, & DeRisi JL (2016). Zika virus cell tropism in the developing human brain and inhibition by azithromycin. </span><span style="font-style: italic;">Proceedings of the National Academy of Sciences of the United States of America, 113</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> (50), 14408-14413 PMID: </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/27911847" rev="review" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;">27911847</a></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27453325&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Comparative+Analysis+Between+Flaviviruses+Reveals+Specific+Neural+Stem+Cell+Tropism+for+Zika+Virus+in+the+Mouse+Developing+Neocortex.&rft.issn=&rft.date=2016&rft.volume=10&rft.issue=&rft.spage=71&rft.epage=6&rft.artnum=&rft.au=Brault+JB&rft.au=Khou+C&rft.au=Basset+J&rft.au=Coquand+L&rft.au=Fraisier+V&rft.au=Frenkiel+MP&rft.au=Goud+B&rft.au=Manuguerra+JC&rft.au=Pardigon+N&rft.au=Baffet+AD&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
<div style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27453325&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Comparative+Analysis+Between+Flaviviruses+Reveals+Specific+Neural+Stem+Cell+Tropism+for+Zika+Virus+in+the+Mouse+Developing+Neocortex.&rft.issn=&rft.date=2016&rft.volume=10&rft.issue=&rft.spage=71&rft.epage=6&rft.artnum=&rft.au=Brault+JB&rft.au=Khou+C&rft.au=Basset+J&rft.au=Coquand+L&rft.au=Fraisier+V&rft.au=Frenkiel+MP&rft.au=Goud+B&rft.au=Manuguerra+JC&rft.au=Pardigon+N&rft.au=Baffet+AD&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Brault JB, Khou C, Basset J, Coquand L, Fraisier V, Frenkiel MP, Goud B, Manuguerra JC, Pardigon N, & Baffet AD (2016). Comparative Analysis Between Flaviviruses Reveals Specific Neural Stem Cell Tropism for Zika Virus in the Mouse Developing Neocortex. <span style="font-style: italic;">EBioMedicine, 10</span>, 71-6 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27453325" rev="review">27453325</a></span> </span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F27759009&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ZIKA+virus+reveals+broad+tissue+and+cell+tropism+during+the+first+trimester+of+pregnancy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=35296&rft.epage=&rft.artnum=&rft.au=El+Costa+H&rft.au=Gouilly+J&rft.au=Mansuy+JM&rft.au=Chen+Q&rft.au=Levy+C&rft.au=Cartron+G&rft.au=Veas+F&rft.au=Al-Daccak+R&rft.au=Izopet+J&rft.au=Jabrane-Ferrat+N&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
<div style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F27759009&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ZIKA+virus+reveals+broad+tissue+and+cell+tropism+during+the+first+trimester+of+pregnancy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=35296&rft.epage=&rft.artnum=&rft.au=El+Costa+H&rft.au=Gouilly+J&rft.au=Mansuy+JM&rft.au=Chen+Q&rft.au=Levy+C&rft.au=Cartron+G&rft.au=Veas+F&rft.au=Al-Daccak+R&rft.au=Izopet+J&rft.au=Jabrane-Ferrat+N&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">El Costa H, Gouilly J, Mansuy JM, Chen Q, Levy C, Cartron G, Veas F, Al-Daccak R, Izopet J, & Jabrane-Ferrat N (2016). ZIKA virus reveals broad tissue and cell tropism during the first trimester of pregnancy. <span style="font-style: italic;">Scientific reports, 6</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27759009" rev="review">27759009</a></span> </span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27247001&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Placental+Macrophages.&rft.issn=1931-3128&rft.date=2016&rft.volume=20&rft.issue=1&rft.spage=83&rft.epage=90&rft.artnum=&rft.au=Quicke+KM&rft.au=Bowen+JR&rft.au=Johnson+EL&rft.au=McDonald+CE&rft.au=Ma+H&rft.au=O%27Neal+JT&rft.au=Rajakumar+A&rft.au=Wrammert+J&rft.au=Rimawi+BH&rft.au=Pulendran+B&rft.au=Schinazi+RF&rft.au=Chakraborty+R&rft.au=Suthar+MS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
<div style="text-align: justify;">
<span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27247001&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Placental+Macrophages.&rft.issn=1931-3128&rft.date=2016&rft.volume=20&rft.issue=1&rft.spage=83&rft.epage=90&rft.artnum=&rft.au=Quicke+KM&rft.au=Bowen+JR&rft.au=Johnson+EL&rft.au=McDonald+CE&rft.au=Ma+H&rft.au=O%27Neal+JT&rft.au=Rajakumar+A&rft.au=Wrammert+J&rft.au=Rimawi+BH&rft.au=Pulendran+B&rft.au=Schinazi+RF&rft.au=Chakraborty+R&rft.au=Suthar+MS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Quicke KM, Bowen JR, Johnson EL, McDonald CE, Ma H, O'Neal JT, Rajakumar A, Wrammert J, Rimawi BH, Pulendran B, Schinazi RF, Chakraborty R, & Suthar MS (2016). Zika Virus Infects Human Placental Macrophages. <span style="font-style: italic;">Cell host & microbe, 20</span> (1), 83-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27247001" rev="review">27247001</a></span> </span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;">Delvecchio R, Higa LM, Pezzuto P, Valadão AL, Garcez PP, Monteiro FL, Loiola EC, Dias AA, Silva FJ, Aliota MT, Caine EA, Osorio JE, Bellio M, O'Connor DH, Rehen S, de Aguiar RS, Savarino A, Campanati L, & Tanuri A (2016). Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models. <span style="font-style: italic;">Viruses, 8</span> (12) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27916837" rev="review">27916837</a></span></span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27912091&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Genetic+Ablation+of+AXL+Does+Not+Protect+Human+Neural+Progenitor+Cells+and+Cerebral+Organoids+from+Zika+Virus+Infection.&rft.issn=1934-5909&rft.date=2016&rft.volume=19&rft.issue=6&rft.spage=703&rft.epage=708&rft.artnum=&rft.au=Wells+MF&rft.au=Salick+MR&rft.au=Wiskow+O&rft.au=Ho+DJ&rft.au=Worringer+KA&rft.au=Ihry+RJ&rft.au=Kommineni+S&rft.au=Bilican+B&rft.au=Klim+JR&rft.au=Hill+EJ&rft.au=Kane+LT&rft.au=Ye+C&rft.au=Kaykas+A&rft.au=Eggan+K&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+Reports&rft_id=info%3Adoi%2F10.1016%2Fj.celrep.2016.05.074&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+IFITMs+Inhibit+Zika+Virus+Replication&rft.issn=22111247&rft.date=2016&rft.volume=15&rft.issue=11&rft.spage=2323&rft.epage=2330&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124716306878&rft.au=Savidis%2C+G.&rft.au=Perreira%2C+J.&rft.au=Portmann%2C+J.&rft.au=Meraner%2C+P.&rft.au=Guo%2C+Z.&rft.au=Green%2C+S.&rft.au=Brass%2C+A.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Savidis, G., Perreira, J., Portmann, J., Meraner, P., Guo, Z., Green, S., & Brass, A. (2016). The IFITMs Inhibit Zika Virus Replication <span style="font-style: italic;">Cell Reports, 15</span> (11), 2323-2330 DOI: <a href="http://dx.doi.org/10.1016/j.celrep.2016.05.074" rev="review">10.1016/j.celrep.2016.05.074</a></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+pathogens&rft_id=info%3Apmid%2F24699674&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=IFITM3+restricts+influenza+A+virus+entry+by+blocking+the+formation+of+fusion+pores+following+virus-endosome+hemifusion.&rft.issn=1553-7366&rft.date=2014&rft.volume=10&rft.issue=4&rft.spage=&rft.epage=&rft.artnum=&rft.au=Desai+TM&rft.au=Marin+M&rft.au=Chin+CR&rft.au=Savidis+G&rft.au=Brass+AL&rft.au=Melikyan+GB&rfe_dat=bpr3.included=1;bpr3.tags=">Desai TM, Marin M, Chin CR, Savidis G, Brass AL, & Melikyan GB (2014). IFITM3 restricts influenza A virus entry by blocking the formation of fusion pores following virus-endosome hemifusion. <span style="font-style: italic;">PLoS pathogens, 10</span> (4) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24699674" rev="review">24699674</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F21501828&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+soluble+serum+protein+Gas6+bridges+virion+envelope+phosphatidylserine+to+the+TAM+receptor+tyrosine+kinase+Axl+to+mediate+viral+entry.&rft.issn=1931-3128&rft.date=2011&rft.volume=9&rft.issue=4&rft.spage=286&rft.epage=98&rft.artnum=&rft.au=Morizono+K&rft.au=Xie+Y&rft.au=Olafsen+T&rft.au=Lee+B&rft.au=Dasgupta+A&rft.au=Wu+AM&rft.au=Chen+IS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F21501828&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+soluble+serum+protein+Gas6+bridges+virion+envelope+phosphatidylserine+to+the+TAM+receptor+tyrosine+kinase+Axl+to+mediate+viral+entry.&rft.issn=1931-3128&rft.date=2011&rft.volume=9&rft.issue=4&rft.spage=286&rft.epage=98&rft.artnum=&rft.au=Morizono+K&rft.au=Xie+Y&rft.au=Olafsen+T&rft.au=Lee+B&rft.au=Dasgupta+A&rft.au=Wu+AM&rft.au=Chen+IS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Morizono K, Xie Y, Olafsen T, Lee B, Dasgupta A, Wu AM, & Chen IS (2011). The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry. <span style="font-style: italic;">Cell host & microbe, 9</span> (4), 286-98 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21501828" rev="review">21501828</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F23084921&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+TIM+and+TAM+families+of+phosphatidylserine+receptors+mediate+dengue+virus+entry.&rft.issn=1931-3128&rft.date=2012&rft.volume=12&rft.issue=4&rft.spage=544&rft.epage=57&rft.artnum=&rft.au=Meertens+L&rft.au=Carnec+X&rft.au=Lecoin+MP&rft.au=Ramdasi+R&rft.au=Guivel-Benhassine+F&rft.au=Lew+E&rft.au=Lemke+G&rft.au=Schwartz+O&rft.au=Amara+A&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F23084921&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+TIM+and+TAM+families+of+phosphatidylserine+receptors+mediate+dengue+virus+entry.&rft.issn=1931-3128&rft.date=2012&rft.volume=12&rft.issue=4&rft.spage=544&rft.epage=57&rft.artnum=&rft.au=Meertens+L&rft.au=Carnec+X&rft.au=Lecoin+MP&rft.au=Ramdasi+R&rft.au=Guivel-Benhassine+F&rft.au=Lew+E&rft.au=Lemke+G&rft.au=Schwartz+O&rft.au=Amara+A&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Meertens L, Carnec X, Lecoin MP, Ramdasi R, Guivel-Benhassine F, Lew E, Lemke G, Schwartz O, & Amara A (2012). The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. <span style="font-style: italic;">Cell host & microbe, 12</span> (4), 544-57 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/23084921" rev="review">23084921</a></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Redox+biology&rft_id=info%3Apmid%2F25625584&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=NLRP3+inflammasome%3A+from+a+danger+signal+sensor+to+a+regulatory+node+of+oxidative+stress+and+inflammatory+diseases.&rft.issn=&rft.date=2015&rft.volume=4&rft.issue=&rft.spage=296&rft.epage=307&rft.artnum=&rft.au=Abderrazak+A&rft.au=Syrovets+T&rft.au=Couchie+D&rft.au=El+Hadri+K&rft.au=Friguet+B&rft.au=Simmet+T&rft.au=Rouis+M&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Redox+biology&rft_id=info%3Apmid%2F25625584&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=NLRP3+inflammasome%3A+from+a+danger+signal+sensor+to+a+regulatory+node+of+oxidative+stress+and+inflammatory+diseases.&rft.issn=&rft.date=2015&rft.volume=4&rft.issue=&rft.spage=296&rft.epage=307&rft.artnum=&rft.au=Abderrazak+A&rft.au=Syrovets+T&rft.au=Couchie+D&rft.au=El+Hadri+K&rft.au=Friguet+B&rft.au=Simmet+T&rft.au=Rouis+M&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Abderrazak A, Syrovets T, Couchie D, El Hadri K, Friguet B, Simmet T, & Rouis M (2015). NLRP3 inflammasome: from a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. <span style="font-style: italic;">Redox biology, 4</span>, 296-307 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25625584" rev="review">25625584</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F23954153&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Enveloped+viruses+disable+innate+immune+responses+in+dendritic+cells+by+direct+activation+of+TAM+receptors.&rft.issn=1931-3128&rft.date=2013&rft.volume=14&rft.issue=2&rft.spage=136&rft.epage=47&rft.artnum=&rft.au=Bhattacharyya+S&rft.au=Zag%C3%B3rska+A&rft.au=Lew+ED&rft.au=Shrestha+B&rft.au=Rothlin+CV&rft.au=Naughton+J&rft.au=Diamond+MS&rft.au=Lemke+G&rft.au=Young+JA&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F23954153&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Enveloped+viruses+disable+innate+immune+responses+in+dendritic+cells+by+direct+activation+of+TAM+receptors.&rft.issn=1931-3128&rft.date=2013&rft.volume=14&rft.issue=2&rft.spage=136&rft.epage=47&rft.artnum=&rft.au=Bhattacharyya+S&rft.au=Zag%C3%B3rska+A&rft.au=Lew+ED&rft.au=Shrestha+B&rft.au=Rothlin+CV&rft.au=Naughton+J&rft.au=Diamond+MS&rft.au=Lemke+G&rft.au=Young+JA&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Bhattacharyya S, Zagórska A, Lew ED, Shrestha B, Rothlin CV, Naughton J, Diamond MS, Lemke G, & Young JA (2013). Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. <span style="font-style: italic;">Cell host & microbe, 14</span> (2), 136-47 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/23954153" rev="review">23954153</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F27807228&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=TIM-1+Promotes+Hepatitis+C+Virus+Cell+Attachment+and+Infection.&rft.issn=0022-538X&rft.date=2017&rft.volume=91&rft.issue=2&rft.spage=&rft.epage=&rft.artnum=&rft.au=Wang+J&rft.au=Qiao+L&rft.au=Hou+Z&rft.au=Luo+G&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F27807228&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=TIM-1+Promotes+Hepatitis+C+Virus+Cell+Attachment+and+Infection.&rft.issn=0022-538X&rft.date=2017&rft.volume=91&rft.issue=2&rft.spage=&rft.epage=&rft.artnum=&rft.au=Wang+J&rft.au=Qiao+L&rft.au=Hou+Z&rft.au=Luo+G&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Wang J, Qiao L, Hou Z, & Luo G (2017). TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection. <span style="font-style: italic;">Journal of virology, 91</span> (2) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27807228" rev="review">27807228</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Autophagy&rft_id=info%3Apmid%2F27780404&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Autophagy+induced+by+AXL+receptor+tyrosine+kinase+alleviates+acute+liver+injury+via+inhibition+of+NLRP3+inflammasome+activation+in+mice.&rft.issn=1554-8627&rft.date=2016&rft.volume=12&rft.issue=12&rft.spage=2326&rft.epage=2343&rft.artnum=&rft.au=Han+J&rft.au=Bae+J&rft.au=Choi+CY&rft.au=Choi+SP&rft.au=Kang+HS&rft.au=Jo+EK&rft.au=Park+J&rft.au=Lee+YS&rft.au=Moon+HS&rft.au=Park+CG&rft.au=Lee+MS&rft.au=Chun+T&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: small;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Autophagy&rft_id=info%3Apmid%2F27780404&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Autophagy+induced+by+AXL+receptor+tyrosine+kinase+alleviates+acute+liver+injury+via+inhibition+of+NLRP3+inflammasome+activation+in+mice.&rft.issn=1554-8627&rft.date=2016&rft.volume=12&rft.issue=12&rft.spage=2326&rft.epage=2343&rft.artnum=&rft.au=Han+J&rft.au=Bae+J&rft.au=Choi+CY&rft.au=Choi+SP&rft.au=Kang+HS&rft.au=Jo+EK&rft.au=Park+J&rft.au=Lee+YS&rft.au=Moon+HS&rft.au=Park+CG&rft.au=Lee+MS&rft.au=Chun+T&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Han J, Bae J, Choi CY, Choi SP, Kang HS, Jo EK, Park J, Lee YS, Moon HS, Park CG, Lee MS, & Chun T (2016). Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice. <span style="font-style: italic;">Autophagy, 12</span> (12), 2326-2343 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27780404" rev="review">27780404</a></span></span> </span><br />
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<span class="Z3988" style="font-family: "trebuchet ms" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+Reports&rft_id=info%3Adoi%2F10.1016%2Fj.celrep.2016.12.068&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Screening+Bioactives+Reveals+Nanchangmycin+as+a+Broad+Spectrum+Antiviral+Active+against+Zika+Virus&rft.issn=22111247&rft.date=2017&rft.volume=18&rft.issue=3&rft.spage=804&rft.epage=815&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124716317752&rft.au=Rausch%2C+K.&rft.au=Hackett%2C+B.&rft.au=Weinbren%2C+N.&rft.au=Reeder%2C+S.&rft.au=Sadovsky%2C+Y.&rft.au=Hunter%2C+C.&rft.au=Schultz%2C+D.&rft.au=Coyne%2C+C.&rft.au=Cherry%2C+S.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Rausch, K., Hackett, B., Weinbren, N., Reeder, S., Sadovsky, Y., Hunter, C., Schultz, D., Coyne, C., & Cherry, S. (2017). Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus <span style="font-style: italic;">Cell Reports, 18</span> (3), 804-815 DOI: <a href="http://dx.doi.org/10.1016/j.celrep.2016.12.068" rev="review">10.1016/j.celrep.2016.12.068</a></span>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com9tag:blogger.com,1999:blog-8715161762555608131.post-45059502528735766542016-12-14T21:40:00.000-05:002016-12-14T21:40:35.169-05:00ZIKV replication and the induction of p53: a tale of three places ? <div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;">Zika Virus (ZIKV) is a
mosquitoe-borne Flavivirus (MBFV), related to other Flavivirus’ that are
transmitted by mosquitoes such as Dengue Virus (DENV), Yellow Fever Virus (YFV)
or Tick Borne Encephalitis Virus (TBEV) and as such the viral genome is
released into the cytoplasm following viral entry and translated into a single
polyprotein that is cleaved by both viral and cellular proteases into the 3
structural and 7 non-structural proteins.<o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;">One of the characteristic
features of positive strand RNA viruses is the interaction of proteins that are
involved with viral replication with cellular membranes thus leading to the
formation of viral replication centers (RC) in infected cells as discussed <i style="mso-bidi-font-style: normal;">in extensio</i> before for Coronavirus’ and
Chikungunya Virus (CHIKV). In general, the viral RC contain not viral proteins
such as the RNA dependent RNA Polymerase and viral helicase but also dsRNA,
thus shielding viral RNA from being recognized by components of the cellular
antiviral signalling pathway that recognize viral dsRNA such as RIG-1 and MDA-5
as well as providing a scaffold for the assembly for viral particles. In the
case of DENV, WNV, and TBEV, Electron Tomography (ET) studies revealed the
presence of different virus induced structures derived from the ER such as cytoplasmic
vesicles containing viral proteins and dsRNA that appear to be derived from
invaginations of the ER as well as vesicular structures that contain viral
proteins within the ER lumen that appear as invaginations of the ER bearing
pore-like connections to the cytoplasm as indicated by the co-localisation of
either DENV NS1 and NS5 protein or TBEV NS1 protein<span style="mso-spacerun: yes;"> </span>as well as dsRNA with the ER marker Protein
Disulfide Isomerase-1 (PDI), indicating that assembly of the viral RC does take
place at the ER but not within the ER of infected cells or BHK-21 cells
transfected with a TBEV replicon respectively. As indicated by specific
labeling of newly synthesized viral RNA using a MS2 tag, RNA synthesis takes
place within ER derived vesicles that are ER invaginations which are connected
to the cytoplasm via pore forming channels which – in WNV infected C6/36 cells-
are positive for NS3 and NS5. Nascent viral RNA is probably transferred from
the sites of viral RNA synthesis to the assembly site by the viral C
protein.<span style="mso-spacerun: yes;"> </span>It should be noted that
vesicular structures in TBEV infected BHK-21 cells do not stain positive for
dsRNA, NS3 or NS5 proteins but for the viral E and NS1 protein indicating that
these vesicular structures might indeed either fuse with viral RNA containing
vesicles or that viral RNA is transferred. <o:p></o:p></span></span></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;">Like other mosquitoe
borne Flavivirus’, the infection of mosquitoe salivary gland lineage cells
(C6/36) cells that are derived from <i style="mso-bidi-font-style: normal;">Aedes
Albopictus</i> as well as human neuroblastoma (SK-N-SH) cells with ZIKV Paraiba
2015 induce a rearrangement and expansion of the ER with extensive localisation
of the viral E protein throughout the cytoplasm and the ER at 72 hrs p.i. with
dsRNA present within the ER, indicating that similar to WNV MRC MRM61C infected
BHK-21 and DENV-2 infected C6/36 cells,<span style="mso-spacerun: yes;"> </span>ZIKV
RNA is synthesized at the nuclear membrane and within ER invaginations both in
C6/36 and SK-N-SH cells with virions intermixed with dsRNA positive vesicles
thus indicating that both viral RNA synthesis and assembly of virions are taking
place in close proximity during ZIKV replication. <o:p></o:p></span></span></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;"><span lang="EN-US">Interestingly, the
expansion of the ER, the levels of the viral E protein, the amount of dsRNA
staining as well as viral titres despite being similar in pattern and amount in
in C6/36 and SK-N-SH cells are delayed by 24 hrs in C6/36. One factor might be
that in C6/36 cells ZIKV proteins might inhibit antiviral signalling more
efficiently than in mammalian cells or that viral entry in C6/36 cells differs
from mammalian thus leading to an activation of antiviral signalling pathways
that delay viral replication. Interestingly, CCL-125 cells that are derived
from <i style="mso-bidi-font-style: normal;">Aedes Agypti</i> do not support the
replication of ZIKV Paraiba 2015, suggesting that indeed either viral entry or
viral replication is restricted by host specific factors although female <i style="mso-bidi-font-style: normal;">Aedes Agypti</i> mosquitoes support the
replication of ZIKV </span>BRPE243/2015 and
ZIKV /SPH/2015.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;">In
accordance with results obtained in from primary human neuronal cells and from
foetal mice brains, the infection of both SK<span lang="EN-US">-N-SH and C6/36 with ZIKV
Paraiba 2015 induces caspase-3 dependent apoptosis as early as 48 hrs pi. which
is preceded by the release of cytochrome-c and mitochondrial depolarisation. In
contrast to SK-N-SH cells, C6/36 cells only exhibit a small percentage of cells
undergoing apoptosis as indicated by the absence of TUNEL positive cells,
indicating that ZIKV might persist in these cells. Considering that the
infection of CCL-115 cells with ZIKV Paraiba induces low levels of viral
titres, the inhibition of ZIKV replication in CCL-115 cells whilst not complete
might prevent apoptosis (maybe by inducing mitophagy of damaged mitochondria)
of infected cells and thus allow the transfer of viral particles to humans. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;"><span lang="EN-US">Following the infection
with either DENV-2, </span>Semliki Forest Virus
(SFV), Bunyamwera Virus <span lang="EN-US">or Chikungunya Virus (CHIKV), mosquitoe salivary gland
cells produce cytokines that promote the migration of monocyte derived
macrophages not only in infected mosquitoes but also following a blood meal in
hosts, thus facilitating the infection of those cells, suggesting that despite
low viral titres the amount of viral particles might be sufficient to infect
human cells, aided by cytokines. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<b style="mso-bidi-font-weight: normal;"><span lang="EN-US"><span style="font-family: Verdana, sans-serif;"><span style="color: #660000;">Role
of p53 in activating ZIKV induced apoptosis</span><o:p></o:p></span></span></b></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;">In ZIKV Paraiba 2015
infected C6/36 and SK-N-SH cells the ER is enlarged indicating ER stress,
although it is not clear if the enlargement is dependent on the induction of
the UPR by viral proteins such as the viral E, NS4a or prM proteins (similar to
DENV) resulting in the formation of autophagosomes (as observed in Varicella
Zoster Virus (VZV) infected cells) or not. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;"><span lang="EN-US">As discussed before <i style="mso-bidi-font-style: normal;">in extensio</i>, the expression of viral
proteins derived from a variety of positive strand RNA viruses including CHIKV
and Japanese Encephalitis Virus (JEV) induces the ER stress response that can
result in </span><a href="http://virologytidbits.blogspot.com/2014/07/japanese-encephalitis-virus-jev-er.html"><span lang="EN-US">increased
formation of autophagosomes</span></a><span lang="EN-US"> in infected cells in a Beclin-1 dependent manner </span><a href="http://virologytidbits.blogspot.com/2014/07/japanese-encephalitis-virus-jev-er.html"><span lang="EN-US">as well as to
apoptosis</span></a><span lang="EN-US"> in a p53 independent manner. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;"><span lang="EN-US">Furthermore, ER stress </span>promotes the expression of the p53 isoform p53/47
thus inducing a G2 arrest by preventing the expression of p21 in HCT-116 cells,
leading to a stabilisation of 14-3-3σ. Indeed, the infection of human Neural Progenitor
Cells (hNPC) with ZIKV MR 766 results in a G2 arrest, suggesting that ZIKV
induced ER stress induces a G2 arrest. p53 can however also be activated in
ZIKV infected cells following the induction of genotoxic stress as a result of
stalled replication forks. In this model, the expression of viral proteins
induces the downregulation of genes associated with the repair of damaged DNA
as well as of genes associated with DNA replication as discussed in a previous
post and which has been demonstrated for ZIKV MR 766 infected hNPC and foetal
brains infected with ZIKV SZ01. In ZIKV H/PF/2013 infected hNPC and human i90c16
(induced pluripotent human neural stem cell that are derived from IMR-90 human
lung fibroblast cells) (nuclear) Ser-15 phosphorylated p53 and active Caspase-3
can be detected as early as 24 hrs p.i. suggesting that ZIKV indeed does induce
the activation of p53 in neural cells. If however p53 is also induced in
mosquitoe cells and if the activation of p53 also induces DNA damage repair
response or if the DDR is abrogated (and induces apoptosis) has not been
determined. ZIKV H/PF/2013 infected i90c16 cells do however display an increase
in γH2AX (H2AX-Ser19) positive foci indicative of replicative stress as well as
indicating failure to induce the repair of ds/ss DNA breaks, which is supported
by findings that mouse foetal brains infected with ZIKV Mex 1-144 exhibit a
decrease in Ki67 positive cells, a decrease of Histone H3-P (Ser-10) positive
cells as well as a decrease in CldU positive cells with an increased cell cycle
length while the percentage of TUNEL positive cells increases slightly,
suggesting that ZIKV Mex 1-144 and ZIKV H/PF/2013 induce replicative stress
which induces apoptosis in a subset of infected neural cells in the developing
foetal brain whilst inhibiting the progression of the cell cycle including
mitotic entry. It should be emphasised however that majority of infected neural
cells might not undergo apoptosis as indicated by observations that the
infection of foetal mice at embryonic day (E) 17.5 with ZIKV Mex 1-144 the
majority of infected cells is TUNEL negative; these results are consistent with
previous observations that ZIKV associated intrauterine growth restriction is
more pronounced in foetal mice that were infected at E 14.5 or earlier. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgBRs4GxbwfZ3Vxeh5tS4W_AsmxBzI6_LvSS2REDvdoJLMCyBgnxLdRANtKT-JBxMd_fiHSaHbY9ZN-DJGz2_GwLSwQRUoBKSz7A5_m6Y-3SQ7AgmfIBWAFBvSgCuKKme_6SuMYn9nmrrw5/s1600/ZIKV+p53+RC+blog.002.jpeg" imageanchor="1"><img border="0" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgBRs4GxbwfZ3Vxeh5tS4W_AsmxBzI6_LvSS2REDvdoJLMCyBgnxLdRANtKT-JBxMd_fiHSaHbY9ZN-DJGz2_GwLSwQRUoBKSz7A5_m6Y-3SQ7AgmfIBWAFBvSgCuKKme_6SuMYn9nmrrw5/s320/ZIKV+p53+RC+blog.002.jpeg" width="320" /></a></span></div>
<div class="p1" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;">In addition to
genotoxic stress, ZIKV might activate p53 by sequestering Mdm2/HDM2 to the
nucleolus similar to WNV Capsid protein since ZIKV antigen(s) have been
described to localise to structures tentatively identified as the nucleolus and/or
nuclear speckles in infected Vero cells and the DENV Capsid protein
co-localises with DAXX in the nucleus, an interaction that has been linked to
the induction of apoptosis by DENV C protein . In this scenario, the expression
of the viral Capsid protein promotes the stabilisation of p53 by sequestering
Mdm2 independent of p19<sup>Arf <span style="mso-spacerun: yes;"> </span></sup>(as
well as by binding inhibitor
of the serine/threonine phosphatase PP2A (<span style="color: windowtext;">I(2)(PP2A)), </span>thus inducing the expression of pro-apoptotic
genes including Bax and subsequently promoting apoptosis via the mitochondrial
pathway. In addition, the cellular nucleolar helicase DDX56 relocalises in WNV
infected cells from the nucleolus to sites of viral replication, indicating
that the infection of cells with WNV does indeed cause nucleolar stress and
thus activation of p53. <span style="mso-spacerun: yes;"> </span><o:p></o:p></span></div>
<div class="p1" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;">The question
remains however if in addition to genotoxic stress and the nucleolar
localisation of the viral Capsid protein the induction of ER stress by the
formation of viral RC contributes to the activation of p53 or if the expression
of the viral NS4A/NS4B proteins promote the degradation of the cellular Filamin
A (FLNA) protein by increasing the nuclear levels of p62/SQSTM-1. In the latter
scenario, the inhibition of ER stress induced autophagy by NS4A/NS4B via the <a href="http://virologytidbits.blogspot.com/2016/10/autophagy-in-csfv-and-zikv-persistence.html">inhibition of PI-3K</a> prevents the degradation of
p62/SQSTM-1 by selective autophagy, facilitating the proteasomal degradation of
nuclear FLNA and thus prevent the recruitment of Rad51 to sites of DNA damage
and subsequent activation of the ATR dependent pathway of DNA repair whilst
promoting the initiation of<span style="mso-spacerun: yes;"> </span>(error
prone) non-homologues end joining (NHEJ) dependent DNA repair. Promoting NHEJ in
the absence of apoptosis therefore might lead to the accumulation of mutations
that resemble those observed in genetic cases of microcephaly as described in a
recent study that compared data from ZIKV H/PF/2013 infected human NPC with three
different mouse models of microcephaly. <o:p></o:p></span></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiI0GFJf2-AuP6hbOBPkfRhDQk002FGYHCrnxd9NPyCMNGV0S7GgAy1bAjnKJo9ratV8o2xl0MPU12V6cl66rjnxv73GdOfHMtcTR_QJorLC7C5W5F6uuMiafKrIEzkItZqCujxW8vpmgZr/s1600/ZIKV+p53+RC+blog.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiI0GFJf2-AuP6hbOBPkfRhDQk002FGYHCrnxd9NPyCMNGV0S7GgAy1bAjnKJo9ratV8o2xl0MPU12V6cl66rjnxv73GdOfHMtcTR_QJorLC7C5W5F6uuMiafKrIEzkItZqCujxW8vpmgZr/s640/ZIKV+p53+RC+blog.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV and p62/SQSTM-1 dependent selective autophagy</td></tr>
</tbody></table>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;">The induction
of ER stress by viral proteins such as NS4A, NS4B, E or prM or the formation of
viral RC therefore might induce apoptosis either in a p53 dependent or
independent pathway (via CHOP), promote the proteasomal degradation of FLNA
(via p62/SQSTM-1) and might prevent DNA repair by facilitating the translocation
of p53 into the cytoplasm by <span lang="EN-US">Glycogen Synthase Kinase-3 β (GSK3β)
dependent phosphorylation of p53 at Ser-376. In contrast, the localisation of
the viral Capsid protein to the nucleus/nucleolus might activate p53 by
sequestering Mdm2/HDM2 into the nucleolus and/or nuclear speckles, thus
promoting the initiation of the DNA damage response (which in the presence of other
viral proteins might be inhibited downstream). In ZIKV infected cells these
processes might be present at different times post infection and/or dependent
on the cell line/ cell type. <o:p></o:p></span></span></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<b style="mso-bidi-font-weight: normal;"><i style="mso-bidi-font-style: normal;"><span lang="EN-US"><span style="font-family: Verdana, sans-serif;"><span style="color: #990000;">ZIKV and G1 cell cycle
arrest: inhibition of CDC-7?</span><o:p></o:p></span></span></i></b></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;">The induction of p53 by
ZIKV following the induction of the ER stress response may not only induce a G2
arrest but also delay the progression from G1 to S phase which is regulated by
two kinases, CDK-2 and CDC-7. As discussed previously, the infection of foetal
mouse brains with ZIKV SZ 01 decreases the expression of genes related to the
initiation and progression of DNA replication and the infection of hNPC with
ZIKV MR 766 decreases the expression of CDK-2, suggesting that ZIKV infection
can indeed at least delay the onset and certainly the progression of S phase
which –as described above- is in accordance with recent results obtained from
ZIKV Mex 1-14 infected mouse brains. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;">CDC-7 is the catalytic
subunit of the Dbf4b dependent Ser/Thr kinase whose expression is inhibited by
p53 via p53 dependent upregulation of miR-192/215 as well as the E3 ubiquitin
ligase Fbxw7β following the treatment of IMR90 fibroblast cells with
Doxorubicin, low doses of Actinomycin D or γ-irradiation. The activation of p53
in ZIKV infected cells therefore might delay the progression of G1 to S phase
by at least two mechanisms; first by downregulating the expression of CDK-2 and
second by inhibiting CDC-7 via the expression of miR-192/195 and Fbxw7β. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US"><o:p><span style="font-family: Verdana, sans-serif;"> </span></o:p></span><b><i><span lang="EN-US"><span style="font-family: Verdana, sans-serif;"><span style="color: #660000;">ZIKV and CD95/Fas: sensitising of infected cells to extrinsic apoptosis?</span></span></span></i></b></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<span style="font-family: Verdana, sans-serif;"><span lang="EN-US">The DENV Capsid protein not only localises to the
nucleus, but also co-localises with Death Associated Protein-6/DAXX in PML
nuclear bodies and induces the expression of CD95/</span><span class="s1"><span lang="EN-US"> </span></span><span style="color: #545454;">TNFRSF6/</span><span lang="EN-US">Fas,
thus inducing apoptosis of HepG2 cells expressing wt DENV Capsid protein but
not DENV Capsid protein variants that do not localise to the nucleus due to </span>K73A/K74A or R85A/K86A mutations
via the induction of Fas dependent activation of Caspase-3 and -9 following
treatment with an anti-Fas/CD95 antibody. <o:p></o:p></span></div>
<div class="p1" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;">It is therefore possible that the infection of
neuronal and non-neuronal cells with ZIKV may trigger the expression of CD95 at
the cell surface thus sensitizing infected cells to apoptosis induced by the
activation of CD95/FasR either in an autocrine manner and/or by FasL expressing
activated T-lymphocytes. <o:p></o:p></span></span></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiWnEur0GRyfEguiGk3fygW3OiUielQaqIhSOLD9eVPq2KlBme5b27DoxvRGrtAvh-2OiuyruhyktIuvLgaivlhciNOiWAkSEz9U_RLLYal8bNBulJ1Gh12ykmR6-Nu4fggHIt01pg427KS/s1600/ZIKV+p53+RC+blog.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiWnEur0GRyfEguiGk3fygW3OiUielQaqIhSOLD9eVPq2KlBme5b27DoxvRGrtAvh-2OiuyruhyktIuvLgaivlhciNOiWAkSEz9U_RLLYal8bNBulJ1Gh12ykmR6-Nu4fggHIt01pg427KS/s640/ZIKV+p53+RC+blog.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV Capsid protein: Relocalising DAXX to nuclear bodies? </td></tr>
</tbody></table>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;">In summary, ZIKV may induce the activation of p53 by
various pathways, including the induction of genotoxic stress as a result of
stalled replication forks, the induction of nucleolar stress by relocalising or
sequestering nucleolar proteins and the activation of the ER stress response as
a result of the formation of viral replication centers, thus resulting in
extending the length of the cell cycle by prolonging S phase and delaying the
progression of G1 to S phase followed by an arrest in G2 phase of the cell
cycle without progressing to Prophase. The localisation of the viral Capsid
protein, similar to the Capsid protein of WNV and DENV, might contribute to the
activation of intrinsic and extrinsic apoptotic pathways by not only redistributing
nucleolar proteins such as Mdm2/HDM2 but also by sequestering <span style="mso-spacerun: yes;"> </span>DAXX in PML bodies respectively thus
sensitizing infected cells to CD95L induced apoptosis. Further research however
is needed to elucidate the contribution of individual viral proteins to these
processes and the involvement of additional cellular proteins. One possibility
is that ZIKV infection prevents the degradation of FAP-1 by inhibiting
p62/SQSTM-1 dependent selective autophagy of FAP-1 thus preventing Fas induced
apoptosis even in the presence of FasL whereas late in infection intrinsic
apoptosis is activated by NS4B as well as the ER stress response and p53. The
expression of the viral NS4A and NS4B might not only inhibit PI3K mediated regulation
of autophagy but also promoting PI3K mediated apoptosis induced by p53 by preventing
Mdm2 mediated degradation of p53, thus enhancing the effects of Mdm2 sequestration
by the viral Capsid protein. Further experiments are however warranted to
confirm this hypothesis.<o:p></o:p></span></span></div>
<div class="p1" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;"><br /></span></span></div>
<div class="p1" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;"><br /></span></span></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgnkC_Bm3crTee8RRBA7ucvlcsI_RrasXwv2dSnaDjYRh6iRA8qzqByXVVLj3M5OL-1W8GBuAEdbUdquPXFlkFVBRQ7voGGI8NF5MEBRjZt06vQuKpM9PCfko_yatmPEzELANgVTCAfHV2k/s1600/ZIKV+p53+RC+blog.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgnkC_Bm3crTee8RRBA7ucvlcsI_RrasXwv2dSnaDjYRh6iRA8qzqByXVVLj3M5OL-1W8GBuAEdbUdquPXFlkFVBRQ7voGGI8NF5MEBRjZt06vQuKpM9PCfko_yatmPEzELANgVTCAfHV2k/s640/ZIKV+p53+RC+blog.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Inhibition of Fas dependent apoptosis by stabilising Fap-1?</td></tr>
</tbody></table>
<div class="p1" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;"><br /></span></span></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<span lang="EN-US"><span style="font-family: Verdana, sans-serif;">In addition to investigating the individual
contribution of viral proteins to ZIKV induced activation of p53 and ZIKV
induced apoptosis, differences between mosquitoe and human derived cell lines
have to be examined as well since the infection of CCL-125 cells with ZIKV
Paraiba 2015 does not produce high viral titres and infected cells do not
undergo viral induced apoptosis, suggesting that either p53 is not activated in
CCL-125 cells or that anti-apoptotic pathways are activated. <span style="font-size: small;"><o:p></o:p></span></span></span></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<div class="p1" style="text-align: justify;">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEja1GR1tpC3t1byjUo4rBOw5PvdomnEdtWRJgnEf9pDv6SQKgk-2McKnmeuJOizCy3lL8ec8T7O1inKErPdYK4dU53HPaZBSWyNYaoSOc2FM1JLx2REgiR992aZs3KNvuBlTRwEUfsWCMG3/s1600/ZIKV+p53+RC+blog.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEja1GR1tpC3t1byjUo4rBOw5PvdomnEdtWRJgnEf9pDv6SQKgk-2McKnmeuJOizCy3lL8ec8T7O1inKErPdYK4dU53HPaZBSWyNYaoSOc2FM1JLx2REgiR992aZs3KNvuBlTRwEUfsWCMG3/s640/ZIKV+p53+RC+blog.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV and the induction of p53 </td></tr>
</tbody></table>
<div class="p1">
<br /></div>
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UnhideWhenUsed="true" QFormat="true" Name="heading 3"/>
<w:LsdException Locked="false" Priority="9" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="heading 4"/>
<w:LsdException Locked="false" Priority="9" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="heading 5"/>
<w:LsdException Locked="false" Priority="9" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="heading 6"/>
<w:LsdException Locked="false" Priority="9" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="heading 7"/>
<w:LsdException Locked="false" Priority="9" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="heading 8"/>
<w:LsdException Locked="false" Priority="9" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="heading 9"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index 9"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" Name="toc 1"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" Name="toc 2"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" Name="toc 3"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" Name="toc 4"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" Name="toc 5"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" Name="toc 6"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" Name="toc 7"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" Name="toc 8"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" Name="toc 9"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="footnote text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="annotation text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="header"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="footer"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="index heading"/>
<w:LsdException Locked="false" Priority="35" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="caption"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="table of figures"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="envelope address"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="envelope return"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="footnote reference"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="annotation reference"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="line number"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="page number"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="endnote reference"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="endnote text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="table of authorities"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="macro"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="toa heading"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 5"/>
<w:LsdException Locked="false" Priority="10" QFormat="true" Name="Title"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Closing"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Signature"/>
<w:LsdException Locked="false" Priority="1" SemiHidden="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Message Header"/>
<w:LsdException Locked="false" Priority="11" QFormat="true" Name="Subtitle"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Date"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Hyperlink"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="FollowedHyperlink"/>
<w:LsdException Locked="false" Priority="22" QFormat="true" Name="Strong"/>
<w:LsdException Locked="false" Priority="20" QFormat="true" Name="Emphasis"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Document Map"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Plain Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="E-mail Signature"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Top of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Bottom of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal (Web)"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Acronym"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Address"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Cite"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Code"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Definition"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Keyboard"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Preformatted"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Sample"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Typewriter"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Variable"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal Table"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="annotation subject"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="No List"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Elegant"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="39" Name="Table Grid"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" Name="Placeholder Text"/>
<w:LsdException Locked="false" Priority="1" QFormat="true" Name="No Spacing"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading"/>
<w:LsdException Locked="false" Priority="61" Name="Light List"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 1"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 1"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 1"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 1"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 1"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Revision"/>
<w:LsdException Locked="false" Priority="34" QFormat="true"
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<w:LsdException Locked="false" Priority="29" QFormat="true" Name="Quote"/>
<w:LsdException Locked="false" Priority="30" QFormat="true"
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<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 1"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 1"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 1"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 1"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 1"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 1"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 1"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 2"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 2"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 2"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 2"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 2"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 2"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 2"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 2"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 2"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 2"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 2"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 3"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 3"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 3"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 3"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 3"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 3"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 3"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 3"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 3"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 3"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 3"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 3"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 3"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 4"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 4"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 4"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 4"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 4"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 4"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 4"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 4"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 4"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 4"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 4"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 4"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 4"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 4"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 5"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 5"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 5"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 5"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 5"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 5"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 5"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 5"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 5"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 5"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 5"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 5"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 5"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 5"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 6"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 6"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 6"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 6"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 6"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 6"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 6"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 6"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 6"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 6"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 6"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 6"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 6"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 6"/>
<w:LsdException Locked="false" Priority="19" QFormat="true"
Name="Subtle Emphasis"/>
<w:LsdException Locked="false" Priority="21" QFormat="true"
Name="Intense Emphasis"/>
<w:LsdException Locked="false" Priority="31" QFormat="true"
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<div style="text-align: justify;">
<span class="Z3988" style="font-family: "verdana" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Neuron&rft_id=info%3Apmid%2F27930910&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+Neurobiology+of+Zika+Virus.&rft.issn=0896-6273&rft.date=2016&rft.volume=92&rft.issue=5&rft.spage=949&rft.epage=958&rft.artnum=&rft.au=Li+H&rft.au=Saucedo-Cuevas+L&rft.au=Shresta+S&rft.au=Gleeson+JG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u>Further reading</u></span></div>
<div style="text-align: justify;">
<span class="Z3988" style="font-family: "verdana" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Neuron&rft_id=info%3Apmid%2F27930910&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+Neurobiology+of+Zika+Virus.&rft.issn=0896-6273&rft.date=2016&rft.volume=92&rft.issue=5&rft.spage=949&rft.epage=958&rft.artnum=&rft.au=Li+H&rft.au=Saucedo-Cuevas+L&rft.au=Shresta+S&rft.au=Gleeson+JG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Neuron&rft_id=info%3Apmid%2F27930910&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+Neurobiology+of+Zika+Virus.&rft.issn=0896-6273&rft.date=2016&rft.volume=92&rft.issue=5&rft.spage=949&rft.epage=958&rft.artnum=&rft.au=Li+H&rft.au=Saucedo-Cuevas+L&rft.au=Shresta+S&rft.au=Gleeson+JG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Li H, Saucedo-Cuevas L, Shresta S, & Gleeson JG (2016). The Neurobiology of Zika Virus. <span style="font-style: italic;">Neuron, 92</span> (5), 949-958 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27930910" rev="review">27930910</a></span> </span></div>
<div style="text-align: justify;">
<span class="Z3988" style="font-family: "verdana" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Current+opinion+in+virology&rft_id=info%3Apmid%2F27936448&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Flavivirus+transmission+focusing+on+Zika.&rft.issn=1879-6257&rft.date=2016&rft.volume=22&rft.issue=&rft.spage=30&rft.epage=35&rft.artnum=&rft.au=Vasilakis+N&rft.au=Weaver+SC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Current+opinion+in+virology&rft_id=info%3Apmid%2F27936448&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Flavivirus+transmission+focusing+on+Zika.&rft.issn=1879-6257&rft.date=2016&rft.volume=22&rft.issue=&rft.spage=30&rft.epage=35&rft.artnum=&rft.au=Vasilakis+N&rft.au=Weaver+SC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Vasilakis N, & Weaver SC (2016). Flavivirus transmission focusing on Zika. <span style="font-style: italic;">Current opinion in virology, 22</span>, 30-35 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27936448" rev="review">27936448</a></span> </span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Virology&rft_id=info%3Apmid%2F27863275&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Cytoarchitecture+of+Zika+virus+infection+in+human+neuroblastoma+and+Aedes+albopictus+cell+lines.&rft.issn=0042-6822&rft.date=2016&rft.volume=501&rft.issue=&rft.spage=54&rft.epage=62&rft.artnum=&rft.au=Offerdahl+DK&rft.au=Dorward+DW&rft.au=Hansen+BT&rft.au=Bloom+ME&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Offerdahl DK, Dorward DW, Hansen BT, & Bloom ME (2016). Cytoarchitecture of Zika virus infection in human neuroblastoma and Aedes albopictus cell lines. <span style="font-style: italic;">Virology, 501</span>, 54-62 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27863275" rev="review">27863275</a></span> </span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Memorias+do+Instituto+Oswaldo+Cruz&rft_id=info%3Apmid%2F27581122&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ultrastructure+of+Zika+virus+particles+in+cell+cultures.&rft.issn=0074-0276&rft.date=2016&rft.volume=111&rft.issue=8&rft.spage=532&rft.epage=4&rft.artnum=&rft.au=Barreto-Vieira+DF&rft.au=Barth+OM&rft.au=Silva+MA&rft.au=Santos+CC&rft.au=Santos+Ada+S&rft.au=F+JB+Filho&rft.au=Filippis+AM&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Barreto-Vieira DF, Barth OM, Silva MA, Santos CC, Santos Ada S, F JB Filho, & Filippis AM (2016). Ultrastructure of Zika virus particles in cell cultures. <span style="font-style: italic;">Memorias do Instituto Oswaldo Cruz, 111</span> (8), 532-4 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27581122" rev="review">27581122</a></span> </span></div>
<div style="text-align: justify;">
<span class="Z3988" style="font-family: "verdana" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F24522909&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ultrastructural+characterization+and+three-dimensional+architecture+of+replication+sites+in+dengue+virus-infected+mosquito+cells.&rft.issn=0022-538X&rft.date=2014&rft.volume=88&rft.issue=9&rft.spage=4687&rft.epage=97&rft.artnum=&rft.au=Junjhon+J&rft.au=Pennington+JG&rft.au=Edwards+TJ&rft.au=Perera+R&rft.au=Lanman+J&rft.au=Kuhn+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F24522909&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ultrastructural+characterization+and+three-dimensional+architecture+of+replication+sites+in+dengue+virus-infected+mosquito+cells.&rft.issn=0022-538X&rft.date=2014&rft.volume=88&rft.issue=9&rft.spage=4687&rft.epage=97&rft.artnum=&rft.au=Junjhon+J&rft.au=Pennington+JG&rft.au=Edwards+TJ&rft.au=Perera+R&rft.au=Lanman+J&rft.au=Kuhn+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Junjhon J, Pennington JG, Edwards TJ, Perera R, Lanman J, & Kuhn RJ (2014). Ultrastructural characterization and three-dimensional architecture of replication sites in dengue virus-infected mosquito cells. <span style="font-style: italic;">Journal of virology, 88</span> (9), 4687-97 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24522909" rev="review">24522909</a></span> </span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F24623440&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dengue+virus-+and+hepatitis+C+virus-induced+replication+and+assembly+compartments%3A+the+enemy+inside--caught+in+the+web.&rft.issn=0022-538X&rft.date=2014&rft.volume=88&rft.issue=11&rft.spage=5907&rft.epage=11&rft.artnum=&rft.au=Chatel-Chaix+L&rft.au=Bartenschlager+R&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Chatel-Chaix L, & Bartenschlager R (2014). Dengue virus- and hepatitis C virus-induced replication and assembly compartments: the enemy inside--caught in the web. <span style="font-style: italic;">Journal of virology, 88</span> (11), 5907-11 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24623440" rev="review">24623440</a></span> </span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Virology&rft_id=info%3Adoi%2F10.1128%2FJVI.00986-10&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+Endoplasmic+Reticulum+Provides+the+Membrane+Platform+for+Biogenesis+of+the+Flavivirus+Replication+Complex&rft.issn=0022-538X&rft.date=2010&rft.volume=84&rft.issue=20&rft.spage=10438&rft.epage=10447&rft.artnum=http%3A%2F%2Fjvi.asm.org%2Flookup%2Fdoi%2F10.1128%2FJVI.00986-10&rft.au=Gillespie%2C+L.&rft.au=Hoenen%2C+A.&rft.au=Morgan%2C+G.&rft.au=Mackenzie%2C+J.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Gillespie, L., Hoenen, A., Morgan, G., & Mackenzie, J. (2010). The Endoplasmic Reticulum Provides the Membrane Platform for Biogenesis of the Flavivirus Replication Complex <span style="font-style: italic;">Journal of Virology, 84</span> (20), 10438-10447 DOI: <a href="http://dx.doi.org/10.1128/JVI.00986-10" rev="review">10.1128/JVI.00986-10</a></span> </span></div>
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<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F23552408&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Three-dimensional+architecture+of+tick-borne+encephalitis+virus+replication+sites+and+trafficking+of+the+replicated+RNA.&rft.issn=0022-538X&rft.date=2013&rft.volume=87&rft.issue=11&rft.spage=6469&rft.epage=81&rft.artnum=&rft.au=Miorin+L&rft.au=Romero-Brey+I&rft.au=Maiuri+P&rft.au=Hoppe+S&rft.au=Krijnse-Locker+J&rft.au=Bartenschlager+R&rft.au=Marcello+A&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Miorin L, Romero-Brey I, Maiuri P, Hoppe S, Krijnse-Locker J, Bartenschlager R, & Marcello A (2013). Three-dimensional architecture of tick-borne encephalitis virus replication sites and trafficking of the replicated RNA. <span style="font-style: italic;">Journal of virology, 87</span> (11), 6469-81 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/23552408" rev="review">23552408</a></span> </span></div>
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<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27545505&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Neural+Progenitors+in+the+Adult+Mouse+Brain+and+Alters+Proliferation.&rft.issn=1934-5909&rft.date=2016&rft.volume=19&rft.issue=5&rft.spage=593&rft.epage=598&rft.artnum=&rft.au=Li+H&rft.au=Saucedo-Cuevas+L&rft.au=Regla-Nava+JA&rft.au=Chai+G&rft.au=Sheets+N&rft.au=Tang+W&rft.au=Terskikh+AV&rft.au=Shresta+S&rft.au=Gleeson+JG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Li H, Saucedo-Cuevas L, Regla-Nava JA, Chai G, Sheets N, Tang W, Terskikh AV, Shresta S, & Gleeson JG (2016). Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation. <span style="font-style: italic;">Cell stem cell, 19</span> (5), 593-598 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27545505" rev="review">27545505</a></span> </span></div>
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<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27524440&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+NS4A+and+NS4B+Proteins+Deregulate+Akt-mTOR+Signaling+in+Human+Fetal+Neural+Stem+Cells+to+Inhibit+Neurogenesis+and+Induce+Autophagy.&rft.issn=1934-5909&rft.date=2016&rft.volume=19&rft.issue=5&rft.spage=663&rft.epage=671&rft.artnum=&rft.au=Liang+Q&rft.au=Luo+Z&rft.au=Zeng+J&rft.au=Chen+W&rft.au=Foo+SS&rft.au=Lee+SA&rft.au=Ge+J&rft.au=Wang+S&rft.au=Goldman+SA&rft.au=Zlokovic+BV&rft.au=Zhao+Z&rft.au=Jung+JU&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Liang Q, Luo Z, Zeng J, Chen W, Foo SS, Lee SA, Ge J, Wang S, Goldman SA, Zlokovic BV, Zhao Z, & Jung JU (2016). Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. <span style="font-style: italic;">Cell stem cell, 19</span> (5), 663-671 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27524440" rev="review">27524440</a></span> </span></div>
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<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Development+%28Cambridge%2C+England%29&rft_id=info%3Apmid%2F27729407&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus+infection+disrupts+neurovascular+development+and+results+in+postnatal+microcephaly+with+brain+damage.&rft.issn=0950-1991&rft.date=2016&rft.volume=143&rft.issue=22&rft.spage=4127&rft.epage=4136&rft.artnum=&rft.au=Shao+Q&rft.au=Herrlinger+S&rft.au=Yang+SL&rft.au=Lai+F&rft.au=Moore+JM&rft.au=Brindley+MA&rft.au=Chen+JF&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Shao Q, Herrlinger S, Yang SL, Lai F, Moore JM, Brindley MA, & Chen JF (2016). Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage. <span style="font-style: italic;">Development (Cambridge, England), 143</span> (22), 4127-4136 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27729407" rev="review">27729407</a></span> </span></div>
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<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+research&rft_id=info%3Apmid%2F27174054&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Vertical+transmission+of+Zika+virus+targeting+the+radial+glial+cells+affects+cortex+development+of+offspring+mice.&rft.issn=1001-0602&rft.date=2016&rft.volume=26&rft.issue=6&rft.spage=645&rft.epage=54&rft.artnum=&rft.au=Wu+KY&rft.au=Zuo+GL&rft.au=Li+XF&rft.au=Ye+Q&rft.au=Deng+YQ&rft.au=Huang+XY&rft.au=Cao+WC&rft.au=Qin+CF&rft.au=Luo+ZG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Wu KY, Zuo GL, Li XF, Ye Q, Deng YQ, Huang XY, Cao WC, Qin CF, & Luo ZG (2016). Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice. <span style="font-style: italic;">Cell research, 26</span> (6), 645-54 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27174054" rev="review">27174054</a></span> </span></div>
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<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Immunity&rft_id=info%3Apmid%2F27332734&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Host+Inflammatory+Response+to+Mosquito+Bites+Enhances+the+Severity+of+Arbovirus+Infection.&rft.issn=1074-7613&rft.date=2016&rft.volume=44&rft.issue=6&rft.spage=1455&rft.epage=69&rft.artnum=&rft.au=Pingen+M&rft.au=Bryden+SR&rft.au=Pondeville+E&rft.au=Schnettler+E&rft.au=Kohl+A&rft.au=Merits+A&rft.au=Fazakerley+JK&rft.au=Graham+GJ&rft.au=McKimmie+CS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Pingen M, Bryden SR, Pondeville E, Schnettler E, Kohl A, Merits A, Fazakerley JK, Graham GJ, & McKimmie CS (2016). Host Inflammatory Response to Mosquito Bites Enhances the Severity of Arbovirus Infection. <span style="font-style: italic;">Immunity, 44</span> (6), 1455-69 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27332734" rev="review">27332734</a></span> </span></div>
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<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+cell+biology&rft_id=info%3Apmid%2F24316673&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Autophagy+variation+within+a+cell+population+determines+cell+fate+through+selective+degradation+of+Fap-1.&rft.issn=1465-7392&rft.date=2014&rft.volume=16&rft.issue=1&rft.spage=47&rft.epage=54&rft.artnum=&rft.au=Gump+JM&rft.au=Staskiewicz+L&rft.au=Morgan+MJ&rft.au=Bamberg+A&rft.au=Riches+DW&rft.au=Thorburn+A&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Gump JM, Staskiewicz L, Morgan MJ, Bamberg A, Riches DW, & Thorburn A (2014). Autophagy variation within a cell population determines cell fate through selective degradation of Fap-1. <span style="font-style: italic;">Nature cell biology, 16</span> (1), 47-54 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24316673" rev="review">24316673</a></span> </span></div>
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<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Free+radical+research&rft_id=info%3Apmid%2F27780373&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=p62%2FSQSTM1+is+required+for+the+protection+against+endoplasmic+reticulum+stress-induced+apoptotic+cell+death.&rft.issn=1071-5762&rft.date=2016&rft.volume=50&rft.issue=12&rft.spage=1408&rft.epage=1421&rft.artnum=&rft.au=Park+JS&rft.au=Oh+SY&rft.au=Lee+DH&rft.au=Lee+YS&rft.au=Sung+SH&rft.au=Ji+HW&rft.au=Lee+MJ&rft.au=Lee+YH&rft.au=Rhee+SG&rft.au=Bae+SH&rfe_dat=bpr3.included=1;bpr3.tags=">Park JS, Oh SY, Lee DH, Lee YS, Sung SH, Ji HW, Lee MJ, Lee YH, Rhee SG, & Bae SH (2016). p62/SQSTM1 is required for the protection against endoplasmic reticulum stress-induced apoptotic cell death. <span style="font-style: italic;">Free radical research, 50</span> (12), 1408-1421 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27780373" rev="review">27780373</a></span> </span></div>
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<span class="Z3988" style="font-family: "verdana" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F23115297&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+West+Nile+virus+capsid+protein+blocks+apoptosis+through+a+phosphatidylinositol+3-kinase-dependent+mechanism.&rft.issn=0022-538X&rft.date=2013&rft.volume=87&rft.issue=2&rft.spage=872&rft.epage=81&rft.artnum=&rft.au=Urbanowski+MD&rft.au=Hobman+TC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: "verdana" , sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F23115297&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+West+Nile+virus+capsid+protein+blocks+apoptosis+through+a+phosphatidylinositol+3-kinase-dependent+mechanism.&rft.issn=0022-538X&rft.date=2013&rft.volume=87&rft.issue=2&rft.spage=872&rft.epage=81&rft.artnum=&rft.au=Urbanowski+MD&rft.au=Hobman+TC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Urbanowski MD, & Hobman TC (2013). The West Nile virus capsid protein blocks apoptosis through a phosphatidylinositol 3-kinase-dependent mechanism. <span style="font-style: italic;">Journal of virology, 87</span> (2), 872-81 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/23115297" rev="review">23115297</a></span> </span></div>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com1tag:blogger.com,1999:blog-8715161762555608131.post-692682510015894972016-11-12T18:52:00.000-05:002016-11-13T11:00:32.724-05:00Neutralizing and non-neutralizing antibodies: Zika Virus and antibody dependent enhancement of infection <div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">Although Zika Virus
(ZIKV) has been isolated in 1947, until recently ZIKV infection was only
associated with relative mild clinical symptoms and sporadic outbreaks in
Africa, Asia, and Oceania. Following the emergence of ZIKV in the Americas
however, maternal ZIKV infections have been associated with congenital
infections of the brain and the CNS as well as with intrauterine growth restriction
(IUGR) of foetuses and possibly also with an increased risk of miscarriage.
ZIKV is therefore unique among the human pathogenic flavivirus’ since neither
Yellow Fever Virus (YFV), Dengue Virus (DENV), West Nile Virus (WNV) or
Japanese Encephalitis Virus (JEV) are transmitted trans-placental, thus
infecting the embryo or foetus<i style="mso-bidi-font-style: normal;"> in utero</i>.
As described before, the infection of both mice and non-human primates with
various ZIKV strains including the original ZIKV MR766 strain as well as
strains from Asia (ZIKV FSS13025), Oceania (ZIKV H/PF/2013) and the Americas
(ZIKV Paraiba 2015) as well as the infection of human placenta explants (ZIKV
MR766 and ZIKV Nica-1/-2 2016) suggest that ZIKV can cross the placenta
probably by infecting maternal cytotrophoblast cells (CTB) and maternal decidual
fibroblast cells combined with placental injury due to the release of
inflammatory cytokines. In addition, it has been proposed that either maternal
antibodies against ZIKV or the closely related DENV might promote the entry of
ZIKV-IgG complexes into cells in a process known as “Antibody-dependent
Enhancement (ADE)”. ADE has been implicated in the development of severe forms
of DENV associated hemorrhagic fever (Dengue hemorrhagic fever, DHF, or Dengue
Shock Syndrome, DSS) which is generally thought to be caused by cross-reactive
but not cross protective antibodies in which the antibodies produced during the
infection with one DENV serotype fail to neutralize viral particles of a
different serotype but instead facilitate the entry of DENV into cells bearing
the Fc</span><span style="font-family: "symbol";">γ </span><span style="font-family: "helvetica";">receptor such as
monocyte derived macrophages or monocyte derived dendritic cells. This
increases viral replication and thus the viral load.</span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;"><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">Both ZIKV PRVABC59 and
ZIKV MR766 replicate in a wide variety of cell lines, including LNCaP cells
(prostate cancer cell line), ARPE19 (retinal cell line), SF268 (neuronal cell
line), RD (muscle cell line), JEG-3 (placental cell line), Caco-2, Hep-2, HLF
(pulmonary cell line) and hepatic Huh-7 cells, thus explaining the presence of
viral RNA in a wide variety of tissues in animals and humans infected with
ZIKV. Furthermore, ZIKV MR766 and ZIKV PRVABC59 can also replicate in DF-1,
RK-13, BHK-21, LLC-MK2, and Vero cells, all of which are nonhuman cell
lines.<span style="mso-spacerun: yes;"> </span></span><span style="font-family: "helvetica";">In contrast, </span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">human myeloid U937 cells do not support the
replication of</span><span lang="EN-US" style="font-family: "helvetica";"> </span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">either ZIKV
H/PF/2013 or </span><span style="font-family: "helvetica";">ZIKV HD78788, with only
less than 0.6% of infected cells staining positive for viral antigen at 48 hrs p.i..
Pre-incubation of ZIKV with convalescent serum from DENV patients increases the
percentage of cells that stain positive for ZIKV to 36.9% (</span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">ZIKV H/PF/2013)
and 59.0% (ZIKV HD78788) respectively whereas the percentage of DENV-2 positive
cells only increases by 13%, suggesting that ZIKV infection of non-permissive
cells can be enhanced by antibodies against DENV-2 which are non-neutralizing. Pretreating
DENV-2 and ZIKV MR766 with a DENV-2 derived antibody (4G2) that recognizes the
E protein from various Flavivirus’ including WNV, JEV and ZIKV, increases viral
replication in Fcγ</span></span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;">R positive THP-1 cells,
indicating that ZIKV MR766 infection in the presence of 4G2 can be enhanced.
These results indicate that ADE might promote the infection of non-permissive
cells with ZIKV either in a strain dependent manner or dependent on the
antibody being used since different antibodies might not only bind ZIKV with
different affinities but also might recognize different epitopes on the viral
surface. </span><span style="font-family: helvetica neue, arial, helvetica, sans-serif;"><o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Detailed epitope mapping of
133 antibodies revealed that broadly speaking three different regions are recognized
by these antibodies, namely the envelope-dimer epitope (EDE)-1, EDE-2 and the
fusion-loop epitope. (FLE). In contrast to EDE-1, binding of antibodies to
EDE-2 is dependent on the presence of an N-linked glycan at Asn153.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In the case of DENV, all
antibodies bind DENV particles as determined by a capture ELISA assay. In the
case of ZIKV however, FLE antibodies only bind to ZIKV H/PF/2013 but not ZIKV
HD78788 whereas both are recognized by EDE-1 and EDE-2 antibodies.<o:p></o:p></span><br />
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjXnPrB8R9KjVb3_e3UGFM4Q7dMh6aZT3q_kNqWhftS8WoeH2ZsYRzqB7SDe51s_W_DYj4h-QvORpyo8vC7XpfF9IGan4udXA1IaSe880160TgIQZZVTceXGEEtqp_qlTsS4gAB6OFuC9n_/s1600/Presentation.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjXnPrB8R9KjVb3_e3UGFM4Q7dMh6aZT3q_kNqWhftS8WoeH2ZsYRzqB7SDe51s_W_DYj4h-QvORpyo8vC7XpfF9IGan4udXA1IaSe880160TgIQZZVTceXGEEtqp_qlTsS4gAB6OFuC9n_/s640/Presentation.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Domains of ZIKV E protein </td></tr>
</tbody></table>
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Furthermore, monoclonal
antibodies to EDE but not FLE can inhibit ADE of ZIKV H/PF/2013 infection in
the presence of DENV serum, indicating that DENV antibodies bind the EDE of
ZIKV and thus promote viral entry in otherwise non-permissive cell lines. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;"><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"><a href="http://virologytidbits.blogspot.com/2016/11/neuroteratogenic-viruses-zikv-placenta.html" target="_blank">As described before</a>,
placental cells do express significant amounts the viral Axl receptor early and
mid-gestation and despite high levels of IFN-</span><span lang="EN-US" style="font-family: "symbol"; mso-ansi-language: EN-US; mso-ascii-font-family: Helvetica; mso-char-type: symbol; mso-hansi-font-family: Helvetica; mso-symbol-font-family: Symbol;"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">l</span></span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">1 low levels
of viral replication can be detected. It might therefore be possible that in
the presence of DENV antibodies or even antibodies against YFV, JEV and WNV,
ADE might increase the entry of ZIKV and thus promote ZIKV replication not only
by increased viral entry but also by inhibiting RLR mediated antiviral
signalling pathways including inhibiting the production of nitric oxide that
otherwise inhibits the viral RNA dependent RNA Polymerase. Further studies
using GFP labelled virus particles should clarify if ADE indeed does increase
viral entry via the Fc</span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">γ</span></span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;">R concomitant
with a localisation to IFITM-2/-3 positive endosomes in both placental and
non-placental cells such U937 or THP-1 cells. Interestingly, the induction of
autophagy with Rapamycin has been reported to decrease DENV-2 replication in U937
cells, suggesting that upon viral entry the majority of viral particles is not
degraded in this cell line; therefore in the absence of DENV antibodies, ZIKV
might either not be able to enter U937 cells due to the absence of the viral
receptor or alternatively viral particles might be degraded, which might be
similar to <a href="http://virologytidbits.blogspot.com/2016/11/neuroteratogenic-viruses-zikv-placenta.html" target="_blank">syncytiotrophoblast (STB) cells infected with ZIKV Nica-1/-2 2016</a>. </span><span style="font-family: helvetica neue, arial, helvetica, sans-serif;"><o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjb2FDd9qRDEbdijSGYlnRF7gsrJg73PhccMXSQvGxeTGBxLPNO9Aq26hUG-BsiECoZVmZLeNToEtH_WVI5hyphenhyphen3txFfIFJZIQ6az0-DTcjElydDz2XkcBZUaLeFqADg-yfxXGc0JBOppS96n/s1600/Presentation.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjb2FDd9qRDEbdijSGYlnRF7gsrJg73PhccMXSQvGxeTGBxLPNO9Aq26hUG-BsiECoZVmZLeNToEtH_WVI5hyphenhyphen3txFfIFJZIQ6az0-DTcjElydDz2XkcBZUaLeFqADg-yfxXGc0JBOppS96n/s640/Presentation.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Non-neutralising antibodies my mediate viral entry in both Axl negative cells (left) and Axl positive cells (right) by ADE </td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKRhutoxxQgK7skdnhTUfxVI6EzfGVC9FB_kDmHplg5TY2e9PgVxzSNAzeTdEsunEQkuYQcIxmNbfxvVg41Cf-7wx5ON_GD7E11lAmO4O5-xq_96RsjbvU-C1YPjW_oXc_nTB4TQ0qG2sf/s1600/Presentation.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKRhutoxxQgK7skdnhTUfxVI6EzfGVC9FB_kDmHplg5TY2e9PgVxzSNAzeTdEsunEQkuYQcIxmNbfxvVg41Cf-7wx5ON_GD7E11lAmO4O5-xq_96RsjbvU-C1YPjW_oXc_nTB4TQ0qG2sf/s640/Presentation.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Neutralising antibodies may promote viral entry and viral degradation in absence of Axl<br />
dependent viral entry </td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In contrast to
non-neutralizing antibodies found in the convalescent sera of DENV patients,
ZIKV specific antibodies that recognize the domain III or the fusion-loop motif
of the viral E protein neutralize ZIKV H/PF/2013, ZIKV Paraiba 2015, ZIKV P6740
(Malaysia), ZIKV Dakar 41519 and to a lesser extent ZIKV MR766 in an ELISA
based assay. More importantly, one antibody, ZIKV-117, prevents intrauterine
growth restriction (IUGR) in the offspring of female Ifnar-1 -/- mice sired
with male Ifnar-1 +/+ mice if treated prior infection with ZIKV Dakar 41529 as
well as increasing the survival of Ifnar-1 -/- mice infected with ZIKV Dakar
41529 if treated either 1 day p.i. or 5 day p.i.. Additionally, viral
replication in foetal placental and brain tissue as well as maternal brain and
serum is decreased, indicating that ZIKV-117 neutralising mAb decreases viral
replication by preventing viral entry via the cellular receptor and by falling
to induce ADE. The question remains however if in animal models DENV derived
non-neutralizing antibodies do increase viral replication in placental cells. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">ADE has been shown to be
responsible for severe cases of DHF in neonates that have been exposed to DENV
antibodies <i style="mso-bidi-font-style: normal;">in utero</i>. Maternal
vaccination against DENV, or a previous maternal DENV/ZIKV infection therefore
might increase the risk of ZIKV related complications in the neonate despite
the absence of congenital infection. Vice versa, neutralizing ZIKV antibodies
might increase the risk for severe forms of DHF since one clone of ZIKV
neutralizing mAb stains DENV-1, DENV-2 and DENV-4 infected C6/36 cells. The
question also remains if neutralizing antibodies in addition to preventing
viral entry via the Axl receptor are internalized via the Fcγ</span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">R and degraded in the lysosome. Instead of promoting
viral replication, this might initiate the presentation of viral antigens in a
MHC Class-I/-II dependent manner. </span><span style="font-family: "helvetica";"><o:p></o:p></span></span></div>
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padding: 5px; text-align: justify;"><u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Further reading</span></u></span>
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"></span><br />
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+pathogens&rft_id=info%3Apmid%2F24039574&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Viral+membrane+fusion+and+nucleocapsid+delivery+into+the+cytoplasm+are+distinct+events+in+some+flaviviruses.&rft.issn=1553-7366&rft.date=2013&rft.volume=9&rft.issue=9&rft.spage=&rft.epage=&rft.artnum=&rft.au=Nour+AM&rft.au=Li+Y&rft.au=Wolenski+J&rft.au=Modis+Y&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Nour AM, Li Y, Wolenski J, & Modis Y (2013). Viral membrane fusion and nucleocapsid delivery into the cytoplasm are distinct events in some flaviviruses. <span style="font-style: italic;">PLoS pathogens, 9</span> (9) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24039574" rev="review">24039574</a></span></div>
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<span style="font-size: large;"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+currents&rft_id=info%3Apmid%2F27660733&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Utility+of+a+Dengue-Derived+Monoclonal+Antibody+to+Enhance+Zika+Infection+In+Vitro.&rft.issn=&rft.date=2016&rft.volume=8&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Charles+AS&rft.au=Christofferson+RC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Charles AS, & Christofferson RC (2016). Utility of a Dengue-Derived Monoclonal Antibody to Enhance Zika Infection In Vitro. <span style="font-style: italic;">PLoS currents, 8</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27660733" rev="review">27660733</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27443522&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Targets+Different+Primary+Human+Placental+Cells%2C+Suggesting+Two+Routes+for+Vertical+Transmission.&rft.issn=1931-3128&rft.date=2016&rft.volume=20&rft.issue=2&rft.spage=155&rft.epage=66&rft.artnum=&rft.au=Tabata+T&rft.au=Petitt+M&rft.au=Puerta-Guardo+H&rft.au=Michlmayr+D&rft.au=Wang+C&rft.au=Fang-Hoover+J&rft.au=Harris+E&rft.au=Pereira+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Tabata T, Petitt M, Puerta-Guardo H, Michlmayr D, Wang C, Fang-Hoover J, Harris E, & Pereira L (2016). Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission. <span style="font-style: italic;">Cell host & microbe, 20</span> (2), 155-66 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27443522" rev="review">27443522</a></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+reports&rft_id=info%3Apmid%2F27268505&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+IFITMs+Inhibit+Zika+Virus+Replication.&rft.issn=&rft.date=2016&rft.volume=15&rft.issue=11&rft.spage=2323&rft.epage=30&rft.artnum=&rft.au=Savidis+G&rft.au=Perreira+JM&rft.au=Portmann+JM&rft.au=Meraner+P&rft.au=Guo+Z&rft.au=Green+S&rft.au=Brass+AL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+reports&rft_id=info%3Apmid%2F27268505&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+IFITMs+Inhibit+Zika+Virus+Replication.&rft.issn=&rft.date=2016&rft.volume=15&rft.issue=11&rft.spage=2323&rft.epage=30&rft.artnum=&rft.au=Savidis+G&rft.au=Perreira+JM&rft.au=Portmann+JM&rft.au=Meraner+P&rft.au=Guo+Z&rft.au=Green+S&rft.au=Brass+AL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Savidis G, Perreira JM, Portmann JM, Meraner P, Guo Z, Green S, & Brass AL (2016). The IFITMs Inhibit Zika Virus Replication. <span style="font-style: italic;">Cell reports, 15</span> (11), 2323-30 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27268505" rev="review">27268505</a></span></span></div>
thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com1tag:blogger.com,1999:blog-8715161762555608131.post-16745485966093345382016-11-07T14:56:00.002-05:002016-11-07T15:58:34.596-05:00Neuroteratogenic Viruses: ZIKV, the placenta and IUGR <div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-fareast-font-family: Batang;">Following the emergence of Zika Virus (ZIKV) in
the Americas in 2015, Brazil became the first country to report an increase in
cases of microcephaly, followed by other countries including Colombia and the
USA and ZIKV associated cases of foetal and neonatal microcephaly have been
reported since elsewhere. ZIKV therefore joins five other neuroteratogenic
viruses that cause neurological disorders in humans in addition to other neuroteratogenic
viruses which have been associated with abnormal neurodevelopment in animals. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-fareast-font-family: Batang;">In humans, the most common infectious
neuroteratogenic agents are summarised by the mnemonic “TORCH(S)”
(Toxoplasmosis, Others, Rubella, (Human) Cytomegalovirus, Herpes Simplex, Syphilis)
with ZIKV either classified as “Others” or by expanding the mnemonic to TORCHSZ
and indeed health authorities in affected countries regularly test cases of
microcephaly suspected to be associated with neurological infections not only
for ZIKV but also for the presence of TORCH(S). Microcephaly however is only
one outcome of CNS defects that are associated with the infection of foetal neural
cells with infectious agents, as illustrated by the wide range of symptoms of
neonate that include hydrocephalus, cerebellar dysplasia, hypomyelinogenesis or
microphthalmia. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; mso-fareast-font-family: Batang;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Common to all pathogens is, that they infect
the foetus <i style="mso-bidi-font-style: normal;">in utero</i> rather than <i style="mso-bidi-font-style: normal;">intra partum</i> or vertical by
breastfeeding, suggesting that the infection of neural precursor or mature neurons
during the development of the foetal brain causes abnormal foetal brain
development.<span style="mso-spacerun: yes;"> </span>Therefore, it is crucial to
examine both the ability of neuroteratogenic viruses to infect and replicate in
vaginal tissue as well to examine the mechanism of transplacental transmission and
thus infection of embryonic and/or foetal cells. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; mso-fareast-font-family: Batang;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi_0sq5a64IveYcW_B1JeyN8hzB6UjZh0f5E2dVdUkSQnqJZvDMR7tA9PsrnPebRjlsMxj-cGr_FiF_APow9iXCWvTRye4VIRXPFvJR9eCGJ2EaUUW3LyJE4CV26Wd4nXDfzCDGBqJ8JLzL/s1600/Viruses+and+neurodegeneration+ZIKV+and+Rabies+.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi_0sq5a64IveYcW_B1JeyN8hzB6UjZh0f5E2dVdUkSQnqJZvDMR7tA9PsrnPebRjlsMxj-cGr_FiF_APow9iXCWvTRye4VIRXPFvJR9eCGJ2EaUUW3LyJE4CV26Wd4nXDfzCDGBqJ8JLzL/s640/Viruses+and+neurodegeneration+ZIKV+and+Rabies+.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table: Neuroteratogenic viruses </td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; mso-fareast-font-family: Batang;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-fareast-font-family: Batang;">In the case of ZIKV, <a href="http://virologytidbits.blogspot.com/2016/10/zikv-and-microcephaly-african-and-asian.html">the
intra vaginal infection of wt</a>, Irf-3 Irf-7 -/-, and Ifnar-1 -/+ pregnant
mice with ZIKV FSS13025 is followed by transplacental transmission of ZIKV with
the offspring of infected mice displaying signs of intrauterine growth restriction
(IUGR). IUGR, signs of microcephaly including extensive apoptosis of cortical progenitor
cells have also been demonstrated in the offspring of mice infected i.p. with
ZIKV BR, suggesting that ZIKV indeed can cross the placenta. Studies in foetal
mice displaying IUGR however frequently display neuronal cells that undergo
virus independent apoptosis, i.e. the absence of viral antigen in neuronal
cells undergoing apoptosis, suggesting that ZIKV infection can also cause
bystander apoptosis and/or tissue injury independent of the initial viral
cytopathic effect. Indeed, a recent study suggests that the infection of
cranial crest neuronal cells (CNCC) with ZIKV MR766 only induces limited
apoptosis of infected CNCC with extensive apoptosis of non-infected cells by
inducing the expression of inflammatory cytokines thus inducing T lymphocyte
dependent cytolysis as well as apoptosis of neighbouring neuronal cells, which
might explain the intracranial calcifications that are commonly seen in cases of
ZIKV associated microcephaly. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<b style="mso-bidi-font-weight: normal;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-fareast-font-family: Batang;">Transplacental
transmission of ZIKV<o:p></o:p></span></b></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-fareast-font-family: Batang;">The placenta constitutes the principal barrier
between the viraemic mother and the non-infected embryo/foetus. In both humans
and mice, chorionic villi are separated from the maternal blood by layers of
placental multinucleate syncytia of trophoblast cells (PTB or STB) and
Cytotrophoblasts(CTB), either by one cell layer (hemomonochorial; primate) or
multiple cell layers (hemotrichorial; mouse), whereas in pigs the chorionic
villi are separated from the maternal blood by the uterine epithelium,
endothelium and connective tissue. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;">In primates, mononuclear extravillious
trophoblasts (distally) extent into the decidua and are thus being exposed to
maternal fibroblasts and leukocytes. The transmigration of leukocytes however
is prevented due to the absence of intercellular junctions of the epithelium. In
addition, STB are also expressing high levels of TLR and thus are capable of
inducing a strong antiviral response as evidenced by high levels of Interferon-delta
type 1 (IFN-𝚫</span><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;">1) infected with ZIKV FSS 13025 or ZIKV MR766
as well as potentially inducing the degradation of endosomes that contain ZIKV
particles by autophagy following viral entry.<span style="mso-spacerun: yes;">
</span>As mentioned above and as discussed in a <a href="http://virologytidbits.blogspot.com/2016/10/zikv-and-microcephaly-african-and-asian.html">previous</a>
post, ZIKV can infect and replicate in cells of the vaginal mucosa. It is
therefore possible that the secretion of inflammatory cytokines can disrupt the
placental barrier and thus infect foetal cells. Alternatively, ZIKV –and other
neuroteratogenic viruses- may infect foetal M2 macrophages (Hofbauer cells)
that express Fc</span><span style="font-family: "symbol"; mso-ascii-font-family: Helvetica; mso-char-type: symbol; mso-fareast-font-family: Batang; mso-hansi-font-family: Helvetica; mso-symbol-font-family: Symbol;"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">g</span></span><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;"> receptors as well as
syncytiotrophoblasts (STB) that express foetal/neonatal Fc receptors (FcRn).
This notion is supported by findings that ZIKV PR 2015 infects both Hofbauer
cells and STB, concomitant with the expression of IFN-</span><span style="font-family: "symbol"; mso-ascii-font-family: Helvetica; mso-char-type: symbol; mso-fareast-font-family: Batang; mso-hansi-font-family: Helvetica; mso-symbol-font-family: Symbol;"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">a</span></span></span><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> and CXLB. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">To investigate if
placental tissue supports the replication of ZIKV and thus can transmit ZIKV to
foetal tissue, organotypic cultures of chorionic or chorionic villus explants
derived from human placental tissues obtained at different times gestation or Amniotic
Epithelial Cells (AmEpC) and other cell lines including Human Placental
Fibroblasts (HPF), Trophoblast Progenitor Cells (TBPC), and Chorionic
Trophoblasts (CTB) obtained from foetal membranes were infected with different
ZIKV strains, namely ZIKV Nica 1-16 (Nicaragua), ZIKV Nica 2-16 (Nicaragua),
ZIKV MR766 (Uganda), ZIKV SBH2015 (Brazil), ZIKV PRVABC59 (Puerto Rico) or ZIKV
FSS13025 (Cambodia) with viral replication being detected by immunofluorescence
analysis for the viral E glycoprotein and the viral nonstructural NS3 protein
as well as determining viral titres by plaque and focus forming assays. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; mso-ansi-language: EN-US;">AmEpC derived from mid-
and late- gestation as well as CTB, TBPC, HPF or Human Umbilical Cord Vein
Endothelial Cells (HUVEC) infected with either ZIKV MR766 or ZIKV Nica 1-16
stained positive both for NS3 and E protein at 72 hrs p.i. indicating that both
ZIKV MR766 and ZIV Nica 1-16 replicate in cells derived from the human
placenta. Furthermore, viral replication was accompanied by the release of
viral particles, although the highest titres were obtained from AmEpC derived
from the human placenta mid gestation infected with ZIKV MR766, ZIKV Nica 1-16
or ZIKV Nica 2-16 strains when compared to HPF, CTB, TBPC or HUVEC, which
confirms previous reports</span><span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> that ZIKV
PR 2015 can infect CTB derived from full term (> 37 weeks) human placentas. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar
to CTB or TBCP, ZIKV MR766 and ZIKV FSS13025 can infect and replicate in
Placental Trophoblast Cell lines such as JEG-3 and HTR-8 although these ZIKV
strains do not replicate in Primary Human Trophoblast Cells (PHT) isolated from
full term placental tissue, indicating that the ability to infect placental
tissue with ZIKV varies during different stages of the pregnancy as well as
between cell types. Indeed, the expression levels of the main ZIKV receptor Axl
and a co-receptor, TIM-1, in AmEpC isolated from mid- to late gestation is
strong with Axl being located at the plasma membrane during mid-gestation and
vesicular during the late stages of gestation, indicating that viral entry
might be inhibited during the later stages of gestation. In TBPC, TIM-1 -a
potential ZIKV co-receptor- is expressed both at 7.3 and 15.6 weeks gestational
stage, whereas the expression of Axl is increased at week 15.6. Primary CTB
however do not express Axl at late stages of gestation (in contrast to mid
stage gestation), suggesting that at this point ZIKV entry might be primarily
mediated by TIM-1. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">Interestingly, ZIKV MR766
infected CTB cease to proliferate as measured by Ki-67 staining, suggesting
that the infection of CTB with ZIKV MR766 induces a cell cycle arrest, which
might be accompanied by the induction of apoptosis or senescence. In contrast
to CTB, syncytiotrophoblasts (STB) do not support viral replication although
the viral E protein can be detected in cytoplasmic vesicles in ZIKV Nica 1-16
infected indicating that viral replication might be inhibited either post-entry
by preventing the release of the viral genome or by degradation of <i style="mso-bidi-font-style: normal;">de novo</i> synthesized viral proteins
probably due to high levels of IFN-</span><span lang="EN-US" style="font-family: "symbol"; mso-ansi-language: EN-US; mso-ascii-font-family: Helvetica; mso-char-type: symbol; mso-hansi-font-family: Helvetica; mso-symbol-font-family: Symbol;"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">l</span></span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">1 as discussed
above and in a previous post as well as the </span></span><span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">other factors such as IFITM-3.</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="font-family: "helvetica";">In
addition to AmEpC, CTB and STB, ZIKV has also been shown to infect primary
decidual fibroblasts (dFibroblasts) as demonstrated by high viral titres
of<span style="mso-spacerun: yes;"> </span>and the presence of ZIKV E protein in
dFibroblasts infected with a ZIKV strain derived from a French patient that got
infected in Brazil (ZIKV FR) 72 hrs p.i..</span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">In addition</span></span><span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> to dFibroblasts, decidual Macrophages are also
susceptible to ZIKV FR, supporting observations that ZIKV PR 2015 <a href="http://virologytidbits.blogspot.com/2016/06/cytopathogenesis-of-zikv-iftm-and-viral.html">can
infect and replicate in placental macrophages</a> (Hofbauer cells). </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";">In
conclusion, ZIKV MR766 and ZIKV Nica1/2-2016 isolates have been demonstrated to
productively infect Amniotic Cell Epithelial Cells (AmEpC), </span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">Trophoblast
Progenitor Cells (TBPC), Chorionic Trophoblasts (CTB), human placental/decidual
Fibroblast cells (HPF/dFibroblasts), dec</span><span style="font-family: "helvetica";">idual
Macrophages and Hofbauer cells particularly if these cells were obtained from
placental tissue early or mid-stage gestation and thus allow the infection of
foetal neuronal progenitor cells or foetal macrophages. Decidual macrophages
play a key role in regulating the vascular remodelling during pregnancy and
secrete a wide range of cytokines including Interleukin-1β, -2, -4, -5, -6, -8,
-10, -13 and TNF-α as well as proteases (matrix metalloproteinase-1, -2, -7,
-9, and -10). The infection of dMacrophages therefore might induce inflammation
and tissue damage following ZIKV infection as well as abnormal vascular
development of the human placenta, thus be at least a contributing factor in
the development of IUGR and potentially in ZIKV associated miscarriages
independent of abnormal neural development.<o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";">Moreover,
the infection of </span><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;">Fc</span><span style="font-family: "symbol"; mso-ascii-font-family: Helvetica; mso-char-type: symbol; mso-fareast-font-family: Batang; mso-hansi-font-family: Helvetica; mso-symbol-font-family: Symbol;"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">g</span></span><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;"> receptor (Fc</span><span style="font-family: "symbol"; mso-ascii-font-family: Helvetica; mso-char-type: symbol; mso-fareast-font-family: Batang; mso-hansi-font-family: Helvetica; mso-symbol-font-family: Symbol;"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">g</span></span><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;"> R) bearing foetal
STB or CTB as well as maternal cells of the basal and parietal decidua
including Hofbauer cells might be enhanced by transcytosis of IgG-ZIKV
complexes consisting of DENV cross reactive antibodies and/or maternal ZIKV antibodies
and ZIKV particles.<span style="mso-spacerun: yes;"> </span>In this instance,
the IgG-ZIKV complex enters the cell via phagocytosis of the complex after the activation
of the Fc</span><span style="font-family: "symbol"; mso-ascii-font-family: Helvetica; mso-char-type: symbol; mso-fareast-font-family: Batang; mso-hansi-font-family: Helvetica; mso-symbol-font-family: Symbol;"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">g</span></span><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;">R which induces the phosphorylation of the
immunoreceptor tyrosine based activation motif (ITAM), thus allowing the
recruitment of Zap70 and Syk family proteins and activation of downstream pathways
(including MAPK, PI3-K,PLC</span><span style="font-family: "symbol"; mso-ascii-font-family: Helvetica; mso-char-type: symbol; mso-fareast-font-family: Batang; mso-hansi-font-family: Helvetica; mso-symbol-font-family: Symbol;"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">g</span></span><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;">, Rho, and Rac). These downstream
pathways in turn contribute to vascular injury due to a “cytokine storm”, the
release of high levels of pro-inflammatory cytokines, thus potentially
contributing to the development of IUGR rather than abnormal brain development.
Further experimental data are however needed to confirm this hypothesis. </span></span><span style="font-family: "helvetica";"><o:p></o:p></span></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica"; mso-fareast-font-family: Batang;"></span></span></span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="-webkit-font-kerning: none;">The uptake of ZIKV into macrophages might also be stimulated by autophagy similar to antibody enhanced uptake of DENV into human pre-basophil/Mast cells.In this case, sub-neutralising antibodies from a prior infection stimulate the uptake of IgG-DENV complexes in both KU812 and HMC-1 cells which can be inhibited by either 3-MA or the expression of a catalytically inactive mutant of Atg4B, Atg4B</span><span style="-webkit-font-kerning: none; line-height: normal;"><sup>C74A</sup></span><span style="-webkit-font-kerning: none;">. It should be noted however that it has not be conclusively proven that autophagy is required for viral uptake; based on the published results, it cannot be ruled out that the IgG-DENV complex increases viral entry via an autophagy independent mechanism and that the inhibition of viral replication by 3-MA or Atg4B</span><span style="-webkit-font-kerning: none; line-height: normal;"><sup>C74A </sup></span><span style="-webkit-font-kerning: none;">occurs by inhibiting the formation of viral replication centres. and/or by inhibiting the antiviral interferon type I signalling pathway. </span></span></div>
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<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Further reading</span></u></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Kim K, & Shresta S (2016). Neuroteratogenic Viruses and Lessons for Zika Virus Models. <span style="font-style: italic;">Trends in microbiology, 24</span> (8), 622-36 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27387029" rev="review">27387029</a> </span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell&rft_id=info%3Apmid%2F27565347&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Vaginal+Exposure+to+Zika+Virus+during+Pregnancy+Leads+to+Fetal+Brain+Infection.&rft.issn=0092-8674&rft.date=2016&rft.volume=166&rft.issue=5&rft.spage=1247&rft.epage=12560000&rft.artnum=&rft.au=Yockey+LJ&rft.au=Varela+L&rft.au=Rakib+T&rft.au=Khoury-Hanold+W&rft.au=Fink+SL&rft.au=Stutz+B&rft.au=Szigeti-Buck+K&rft.au=Van+den+Pol+A&rft.au=Lindenbach+BD&rft.au=Horvath+TL&rft.au=Iwasaki+A&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell&rft_id=info%3Apmid%2F27565347&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Vaginal+Exposure+to+Zika+Virus+during+Pregnancy+Leads+to+Fetal+Brain+Infection.&rft.issn=0092-8674&rft.date=2016&rft.volume=166&rft.issue=5&rft.spage=1247&rft.epage=12560000&rft.artnum=&rft.au=Yockey+LJ&rft.au=Varela+L&rft.au=Rakib+T&rft.au=Khoury-Hanold+W&rft.au=Fink+SL&rft.au=Stutz+B&rft.au=Szigeti-Buck+K&rft.au=Van+den+Pol+A&rft.au=Lindenbach+BD&rft.au=Horvath+TL&rft.au=Iwasaki+A&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Yockey LJ, Varela L, Rakib T, Khoury-Hanold W, Fink SL, Stutz B, Szigeti-Buck K, Van den Pol A, Lindenbach BD, Horvath TL, & Iwasaki A (2016). Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection. <span style="font-style: italic;">Cell, 166</span> (5), 1247-12560000 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27565347" rev="review">27565347</a></span> </span></div>
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<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> </span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27693308&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infection+Induces+Cranial+Neural+Crest+Cells+to+Produce+Cytokines+at+Levels+Detrimental+for+Neurogenesis.&rft.issn=1931-3128&rft.date=2016&rft.volume=20&rft.issue=4&rft.spage=423&rft.epage=428&rft.artnum=&rft.au=Bayless+NL&rft.au=Greenberg+RS&rft.au=Swigut+T&rft.au=Wysocka+J&rft.au=Blish+CA&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Bayless NL, Greenberg RS, Swigut T, Wysocka J, & Blish CA (2016). Zika Virus Infection Induces Cranial Neural Crest Cells to Produce Cytokines at Levels Detrimental for Neurogenesis. <span style="font-style: italic;">Cell host & microbe, 20</span> (4), 423-428 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27693308" rev="review">27693308</a></span> </span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F27759009&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ZIKA+virus+reveals+broad+tissue+and+cell+tropism+during+the+first+trimester+of+pregnancy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=35296&rft.epage=&rft.artnum=&rft.au=El+Costa+H&rft.au=Gouilly+J&rft.au=Mansuy+JM&rft.au=Chen+Q&rft.au=Levy+C&rft.au=Cartron+G&rft.au=Veas+F&rft.au=Al-Daccak+R&rft.au=Izopet+J&rft.au=Jabrane-Ferrat+N&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">El Costa H, Gouilly J, Mansuy JM, Chen Q, Levy C, Cartron G, Veas F, Al-Daccak R, Izopet J, & Jabrane-Ferrat N (2016). ZIKA virus reveals broad tissue and cell tropism during the first trimester of pregnancy. <span style="font-style: italic;">Scientific reports, 6</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27759009" rev="review">27759009</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27443522&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Targets+Different+Primary+Human+Placental+Cells%2C+Suggesting+Two+Routes+for+Vertical+Transmission.&rft.issn=1931-3128&rft.date=2016&rft.volume=20&rft.issue=2&rft.spage=155&rft.epage=66&rft.artnum=&rft.au=Tabata+T&rft.au=Petitt+M&rft.au=Puerta-Guardo+H&rft.au=Michlmayr+D&rft.au=Wang+C&rft.au=Fang-Hoover+J&rft.au=Harris+E&rft.au=Pereira+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Tabata T, Petitt M, Puerta-Guardo H, Michlmayr D, Wang C, Fang-Hoover J, Harris E, & Pereira L (2016). Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission. <span style="font-style: italic;">Cell host & microbe, 20</span> (2), 155-66 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27443522" rev="review">27443522</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27247001&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Placental+Macrophages.&rft.issn=1931-3128&rft.date=2016&rft.volume=20&rft.issue=1&rft.spage=83&rft.epage=90&rft.artnum=&rft.au=Quicke+KM&rft.au=Bowen+JR&rft.au=Johnson+EL&rft.au=McDonald+CE&rft.au=Ma+H&rft.au=O%27Neal+JT&rft.au=Rajakumar+A&rft.au=Wrammert+J&rft.au=Rimawi+BH&rft.au=Pulendran+B&rft.au=Schinazi+RF&rft.au=Chakraborty+R&rft.au=Suthar+MS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Quicke KM, Bowen JR, Johnson EL, McDonald CE, Ma H, O'Neal JT, Rajakumar A, Wrammert J, Rimawi BH, Pulendran B, Schinazi RF, Chakraborty R, & Suthar MS (2016). Zika Virus Infects Human Placental Macrophages. <span style="font-style: italic;">Cell host & microbe, 20</span> (1), 83-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27247001" rev="review">27247001</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27066743&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Type+III+Interferons+Produced+by+Human+Placental+Trophoblasts+Confer+Protection+against+Zika+Virus+Infection.&rft.issn=1931-3128&rft.date=2016&rft.volume=19&rft.issue=5&rft.spage=705&rft.epage=12&rft.artnum=&rft.au=Bayer+A&rft.au=Lennemann+NJ&rft.au=Ouyang+Y&rft.au=Bramley+JC&rft.au=Morosky+S&rft.au=Marques+ET+Jr&rft.au=Cherry+S&rft.au=Sadovsky+Y&rft.au=Coyne+CB&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Bayer A, Lennemann NJ, Ouyang Y, Bramley JC, Morosky S, Marques ET Jr, Cherry S, Sadovsky Y, & Coyne CB (2016). Type III Interferons Produced by Human Placental Trophoblasts Confer Protection against Zika Virus Infection. <span style="font-style: italic;">Cell host & microbe, 19</span> (5), 705-12 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27066743" rev="review">27066743</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=American+journal+of+reproductive+immunology+%28New+York%2C+N.Y.+%3A+1989%29&rft_id=info%3Apmid%2F26750089&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+Role+of+Decidual+Macrophages+During+Normal+and+Pathological+Pregnancy.&rft.issn=1046-7408&rft.date=2016&rft.volume=75&rft.issue=3&rft.spage=298&rft.epage=309&rft.artnum=&rft.au=Ning+F&rft.au=Liu+H&rft.au=Lash+GE&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Ning F, Liu H, & Lash GE (2016). The Role of Decidual Macrophages During Normal and Pathological Pregnancy. <span style="font-style: italic;">American journal of reproductive immunology (New York, N.Y. : 1989), 75</span> (3), 298-309 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26750089" rev="review">26750089</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+leukocyte+biology&rft_id=info%3Apmid%2F26819320&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Decidual+macrophages%3A+key+regulators+of+vascular+remodeling+in+human+pregnancy.&rft.issn=0741-5400&rft.date=2016&rft.volume=100&rft.issue=2&rft.spage=315&rft.epage=25&rft.artnum=&rft.au=Lash+GE&rft.au=Pitman+H&rft.au=Morgan+HL&rft.au=Innes+BA&rft.au=Agwu+CN&rft.au=Bulmer+JN&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Lash GE, Pitman H, Morgan HL, Innes BA, Agwu CN, & Bulmer JN (2016). Decidual macrophages: key regulators of vascular remodeling in human pregnancy. <span style="font-style: italic;">Journal of leukocyte biology, 100</span> (2), 315-25 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26819320" rev="review">26819320</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Seminars+in+reproductive+medicine&rft_id=info%3Apmid%2F17960528&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Cytokines+and+chemokines+during+human+embryo+implantation%3A+roles+in+implantation+and+early+placentation.&rft.issn=1526-8004&rft.date=2007&rft.volume=25&rft.issue=6&rft.spage=437&rft.epage=44&rft.artnum=&rft.au=Salamonsen+LA&rft.au=Hannan+NJ&rft.au=Dimitriadis+E&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Salamonsen LA, Hannan NJ, & Dimitriadis E (2007). Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation. <span style="font-style: italic;">Seminars in reproductive medicine, 25</span> (6), 437-44 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/17960528" rev="review">17960528</a></span> </span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+molecular+biology&rft_id=info%3Apmid%2F27130436&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dengue+Virus+Immunopathogenesis%3A+Lessons+Applicable+to+the+Emergence+of+Zika+Virus.&rft.issn=0022-2836&rft.date=2016&rft.volume=428&rft.issue=17&rft.spage=3429&rft.epage=48&rft.artnum=&rft.au=Olagnier+D&rft.au=Amatore+D&rft.au=Castiello+L&rft.au=Ferrari+M&rft.au=Palermo+E&rft.au=Diamond+MS&rft.au=Palamara+AT&rft.au=Hiscott+J&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Olagnier D, Amatore D, Castiello L, Ferrari M, Palermo E, Diamond MS, Palamara AT, & Hiscott J (2016). Dengue Virus Immunopathogenesis: Lessons Applicable to the Emergence of Zika Virus. <span style="font-style: italic;">Journal of molecular biology, 428</span> (17), 3429-48 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27130436" rev="review">27130436</a></span><br />
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26923481&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Antibody-dependent+enhancement+of+dengue+virus+infection+inhibits+RLR-mediated+Type-I+IFN-independent+signalling+through+upregulation+of+cellular+autophagy.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22303&rft.epage=&rft.artnum=&rft.au=Huang+X&rft.au=Yue+Y&rft.au=Li+D&rft.au=Zhao+Y&rft.au=Qiu+L&rft.au=Chen+J&rft.au=Pan+Y&rft.au=Xi+J&rft.au=Wang+X&rft.au=Sun+Q&rft.au=Li+Q&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Huang X, Yue Y, Li D, Zhao Y, Qiu L, Chen J, Pan Y, Xi J, Wang X, Sun Q, & Li Q (2016). Antibody-dependent enhancement of dengue virus infection inhibits RLR-mediated Type-I IFN-independent signalling through upregulation of cellular autophagy. <span style="font-style: italic;">Scientific reports, 6</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26923481" rev="review">26923481</a></span> </span><br />
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+ONE&rft_id=info%3Adoi%2F10.1371%2Fjournal.pone.0110655&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Autophagy+Facilitates+Antibody-Enhanced+Dengue+Virus+Infection+in+Human+Pre-Basophil%2FMast+Cells&rft.issn=1932-6203&rft.date=2014&rft.volume=9&rft.issue=10&rft.spage=0&rft.epage=&rft.artnum=http%3A%2F%2Fdx.plos.org%2F10.1371%2Fjournal.pone.0110655&rft.au=Fang%2C+Y.&rft.au=Wan%2C+S.&rft.au=Lu%2C+Y.&rft.au=Yao%2C+J.&rft.au=Lin%2C+C.&rft.au=Hsu%2C+L.&rft.au=Brown%2C+M.&rft.au=Marshall%2C+J.&rft.au=Anderson%2C+R.&rft.au=Lin%2C+Y.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Fang, Y., Wan, S., Lu, Y., Yao, J., Lin, C., Hsu, L., Brown, M., Marshall, J., Anderson, R., & Lin, Y. (2014). Autophagy Facilitates Antibody-Enhanced Dengue Virus Infection in Human Pre-Basophil/Mast Cells <span style="font-style: italic;">PLoS ONE, 9</span> (10) DOI: <a href="http://dx.doi.org/10.1371/journal.pone.0110655" rev="review">10.1371/journal.pone.0110655</a></span>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com1tag:blogger.com,1999:blog-8715161762555608131.post-31570052072540445872016-10-18T20:22:00.002-04:002016-10-18T21:40:06.862-04:00Autophagy in CSFV and ZIKV infected cells: persistence versus neurodegenerative disease<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Zika Virus (ZIKV) was
first isolated in 1947 from a sentinel monkey in Uganda and associated with
human infection in 1954 when neutralizing antibodies were detected in the sera
of residents in India, with antibodies also being found in residents from
various African countries. ZIKV is mosquitoe-borne Flavivirus that is
predominantly transmitted via <i style="mso-bidi-font-style: normal;">Aedes
Agypti</i>, although sexual transmission (female to male, male to female, male
to male) and transmission via blood transfusion has also been reported.<o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span lang="EN-US" style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Clinically </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">most cases are
asymptomatic and symptomatic cases only present themselves with relative benign
symptoms in adults, the exception being Guillain Barre Syndrome. During in the
current outbreak in the Americas and –albeit only retroactively identified- in
the 2013/2014 outbreak in French Polynesia, ZIKV has been identified to a
causative agent of abnormal foetal brain development, leading to congenital
defects, namely microcephaly, anomalies of the CNS, miscarriages and in rare
cases foetal and/or neonatal death. Studies in both wt and immunodeficient mice
confirmed that the infection of pregnant mice with various strains of ZIKV
including strains from Asia (SZ01, FSS1305), Oceania (H/PF/2013), Brazil
(Paraiba 2015), <span style="color: black; mso-themecolor: text1;">Puerto Rico
(PRVABC59</span>) and Mexico (MEX_1_7) indeed can cause abnormal development of
the (foetal) brain by apoptosis of neural progenitor cells similar to
representatives of the African strain, ZIKV MR766 (Uganda, 1947) and ZIKV </span></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="color: black; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; mso-themecolor: text1;">IbH30656
(Nigeria, 1968)</span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;">, tested. In addition, the infection of brain organoids, neurospheres,
human (foetal) Neural Progenitor Cells (h (f) NPC) and human Neural Stem Cells
(NSC) with various ZIKV strains including a primary isolate from Africa, ZIKV
ArB41644, demonstrated that ZIKV can indeed induce apoptosis of proliferating
but probably not of mature neurons. Recently the infection of cranial neural
crest cells (CNCC) with either ZIKV MR766 or ZIKV H/PF/2013 has been reported
to induce high levels of cytokines that are detrimental for neurogenesis,
causing bystander apoptosis of uninfected neuronal cells. Infected CNCC do not
undergo apoptosis at 24 hrs p.i. but apoptosis is increased at 72 hrs p.i.
confirming that both ZIKV MR766 and ZIKV H/PF/2013 can induce apoptosis of CNCC
although only approx. 8% of ZIKV infected CNCC undergo apoptosis compared to 4%
of mock or DENV infected CNCC, indicating that CNCC support viral infection
whilst being protected against apoptosis probably by VEGF as indicated by increased
secretion of VEGF which has been shown to inhibit apoptosis of human
microvascular endothelial cells (HUMEC). </span><span style="font-family: 'helvetica neue', arial, helvetica, sans-serif;"> </span><span style="font-family: helvetica neue, arial, helvetica, sans-serif;"><o:p></o:p></span></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In brains of wt C57BL/6
mice intracranial infected with ZIKV MR766 day 7 postnatal and analysed day 4
p.i. brain mass is reduced compared to mock infected mice by 25%, as well as
showing an increase of NeuN<sup>+ <span style="mso-spacerun: yes;"> </span></sup>and
CTIP<sup>+</sup> cells that also positive for active Caspase-3, indicating that
ZIKV MR766 does not or rarely induces apoptosis in corticospinal cells,
neuronal progenitor cells and astrocytes but in mature neurons in postnatal
mice.<span style="mso-spacerun: yes;"> </span>These results are in contrast with
previously discussed results that indicate that in foetal mice, mature neurons
are ZIKV negative and do not undergo apoptosis upon ZIKV infection. In contrast
to mice infected at day 7 postnatal, mice infected at three weeks postnatal do
show less severe apoptosis as measured by the presence of active Caspase-3
although similar to day 7 postnatal infected mice, widespread apoptosis of NeuN<sup>+
</sup>cells is detected by the presence active Caspase-3. When interpreting
these experiments however, one has to bear in mind that ZIKV MR766 is a
neurotrophic strain adapted to mice brain due to repeated intracranial passage.
<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<b style="mso-bidi-font-weight: normal;"><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Autophagy
and viral infection<o:p></o:p></span></b></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Autophagy is a cellular
degradation pathway that involves the sequestration of cytoplasmic component
such as organelles, protein aggregates or pathogens with (transient) double
membrane most commonly derived from the ER, forming a phagosome that ultimately
matures into the autophagosome and is degraded by lysosomal enzymes such as
acidic hydrolases upon fusion with the lysosome. In general, basal autophagy is
part of the turnover of RNA, proteins and organelles but can be induced in
cells undergoing various forms of stress, including starvation. Both genome
wide screens and large scale proteomic basic screens identified a substantial
number of autophagy related regulators, including but not limited to autophagy
related genes (ATG) that initiate the formation and the maturation of
autophagosomes, aided by improved imaging, as well as degrading substrates such
as RNA in lysosomes. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In the case of viral
infections, the interactions between positive sense RNA viruses is of
particular interest since autophagosomes might contribute to the decay of
(viral) RNA in lysosomes by RNase T2, RNASE1 and RNASE6/RNase K6. Although it
has not been determined experimentally, viral RNA might be targeted to
lysosomes directly (similar to LINE 1 via processing bodies/stress granules
that interact with NDP52/CALCOCO2 or p62/SQSTM-1) or as part of a complex with
viral and/or cellular proteins that form a RNA-Protein Binding complex (RBP). <o:p></o:p></span><br />
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi9ofSJRC8pQnR_UCn7yLg5Z2A0WX2qXUCtCNUPIyPXB3oNTgRrB4CmH4D0h4UuuNDnhmjz5owh5T2-vqaFUS8EACcscFpR5q66axzuz3-VoL-QQZNs1j_Bwqqk72-zK_wR6qCxvXVdM6fb/s1600/ZIKV+CSFV+autophagy.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi9ofSJRC8pQnR_UCn7yLg5Z2A0WX2qXUCtCNUPIyPXB3oNTgRrB4CmH4D0h4UuuNDnhmjz5owh5T2-vqaFUS8EACcscFpR5q66axzuz3-VoL-QQZNs1j_Bwqqk72-zK_wR6qCxvXVdM6fb/s640/ZIKV+CSFV+autophagy.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: General outline of the autophagy pathway</td></tr>
</tbody></table>
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">More importantly however,
RNA viruses such as Chikungunya Virus (CHIKV), Coronaviruses’ (CoV), Polio
Virus, Measles Virus, DENV, Hepatitis C Virus (HCV) or Classical Swine Fever
Virus (CSFV) can utilize autophagosomes and/or double membrane vesicles (DMV)
to increase viral replication. As discussed in previous posts, in the case of
CHIKV or CoV, the formation of viral replication centers (RC) is dependent on
the autophagy machinery, including ATG5 and Beclin-1, whilst in others –such as
HCV- autophagy is also required for exit of the mature virions as exosomes. To
prevent degradation of assembled viral particles, viral proteins that inhibit
the fusion of the autophagosome with the lysosome by binding Beclin-1 for
instance are expressed late in the replication cycle. <o:p></o:p></span><br />
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh1LbY4LL6lci64RV8CG1nOMvDHjY22RZuUkwTuoH0t07P0ROIHH4JEgnYJ8J1EGoYoucpiwPIyLMcDN36vZK1c131hrruknb8oWv4OK0pCq-kEiETohza83HEMVp7qy_OrwWO7m10kPVmz/s1600/ZIKV+CSFV+autophagy.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh1LbY4LL6lci64RV8CG1nOMvDHjY22RZuUkwTuoH0t07P0ROIHH4JEgnYJ8J1EGoYoucpiwPIyLMcDN36vZK1c131hrruknb8oWv4OK0pCq-kEiETohza83HEMVp7qy_OrwWO7m10kPVmz/s640/ZIKV+CSFV+autophagy.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Regulation of the autophagy pathway by CoV proteins as an example for the regulation of<br />
autophagy by viral proteins</td></tr>
</tbody></table>
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Autophagy itself can be
activated via the inhibition of the Phosphatidylinositol-3 Kinase
(PI3-K)-Akt-mTOR pathway, thereby inducing the phosphorylation of the ULK-1
complex and subsequently inducing the formation of the phagosome and
autophagosome. This pathway is activated by the binding of growth factors such
as Insulin to their respective cell surface receptor followed by the conversion
of membrane bound Phosphatidylinositol-4’,5’-bisphosphate (PIP<sub>2</sub>) to
Phosphatidylinositol-3’,4’,5’-trisphosphate (PIP<sub>3</sub>) thus recruiting
Akt to the plasma membrane and phosphorylating Akt. Phosphorylated Akt activates
the TSC1/2 complex, the GTPase activating protein (GAP) of Rheb. Activated Rheb
binds and activates the mTOR-Raptor complex, inhibiting the formation of
autophagosomes and thus autophagy. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Indeed, preventing the
phosphorylation of Akt both at Thr 308 and Ser473 reduces the phosphorylation of
mTOR at Ser2448 thus promoting autophagy whereas the ectopic expression of a constitutively
active myristoylated mutant of Akt (Akt3 E17K) inhibits autophagy. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg1l2NntQJH4udQxhwC5BpOBIzxNkuxY9NINdxdyhCYV0sQfNao0u-kKkA14Ps_eP_BpBOI3DzlN1gwLQ39BZnS8I-tN048TYB54oJxBszxbUQZbLrFGYRcj6j3xTP6F5iu7pHzk1H08OHd/s1600/ZIKV+CSFV+autophagy.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg1l2NntQJH4udQxhwC5BpOBIzxNkuxY9NINdxdyhCYV0sQfNao0u-kKkA14Ps_eP_BpBOI3DzlN1gwLQ39BZnS8I-tN048TYB54oJxBszxbUQZbLrFGYRcj6j3xTP6F5iu7pHzk1H08OHd/s640/ZIKV+CSFV+autophagy.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Akt inhibits the formation of autophagosomes via mTORC-1</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The inhibition of autophagy in neuronal cells can induce
neurodegeneration and autophagy defects –including lysosomal defects- have been
implicated in Huntington Disease and ALS as well as in microcephaly and
megalencephaly-polydactyly-polymicrogyria-hydrocephalus. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<b style="mso-bidi-font-weight: normal;"><i style="mso-bidi-font-style: normal;"><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">CSFV and Autophagy: where
autophagy meets viral persistence<o:p></o:p></span></i></b></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Before discussing recent
results concerning ZIKV and autophagy, it is worth examining the role of
autophagy in cells persistently infected with CSFV and how autophagy
contributes to the survival of viral infected cells.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Classical Swine Fever
Virus (CSFV) is positive strand RNA virus which is classified as a Pestivirus
within the <i style="mso-bidi-font-style: normal;">Flaviviridae</i>, causing
highly virulent disease in swine characterized by a high fever, leukopenia and
hemorrhages with a mortality. In infected PK-15 and 3D4/2 cells, CSFV inhibits
the type I Interferon response, leading to persistent infection in the absence
of apoptosis. In a recently published study, CSFV has been shown to induce the
formation of LC3-II positive (mature) autophagosomes as early as 48 hrs p.i.
and both the viral E2 and NS5A proteins have been shown to localise in LC3
positive vesicles as early as 24 hrs p.i. which can be inhibited by
3-Methyladenine (3-MA) as well as by downregulating the expression of either
Beclin-1 or LC3-B suggesting that CSFV does induce the formation of
autophagosomes as well as autophagic flux as evidenced by decreased levels of
p62/SQSTM-1 in CSFV infected PK-5 and 3D4/2 cells. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Autophagy induction by
CSFV however not only increases viral replication –presumably by forming viral
RC- but also decreases viral induced apoptosis and decreasing mRNA levels of
genes related to the type I Interferon response and IFN stimulated genes
(ISG).<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">CSFV induces apoptosis
via activation of the intrinsic apoptotic pathway, i.e. via activation of
Caspase-9 and Caspase-3, by inducing the accumulation of mitochondrial reactive
oxygen species (ROS) if autophagy is inhibited in infected PK-5 and 3D4/2 cells
by shBeclin1 or shLC3 which can be inhibited by either Z-VAD (a pan caspase
inhibitor) or Necrostatin-1 (Nec-1/ROS scavenger). In addition to the intrinsic
pathway, the extrinsic –Caspase-8 dependent- is also triggered in CSFV infected
autophagy deficient cells.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">CSFV induction of
mitochondrial ROS not only induces the activation of apoptosis but also induces
autophagy and thus promotes the clearance of damaged mitochondria via
mitophagy, which is indirectly indicated by the increase of copy numbers of
mitochondrial DNA in autophagy deficient PK-5 and 3D4/2 CSFV infected cells
(flow cytometry using JC-1, NAO or TMRE was not performed) and/or promotes
autophagy in a Nrf-2 dependent manner. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">The accumulation of ROS
in CFSV infected cells also induces antiviral signalling via RIG-1 and MDA-5,
including increased expression of TNF/TNF-α, IFN-β/IFNB1 and FAS/TNFRSF6 in
autophagy deficient CSFV infected cells, thus inducing the extrinsic pathway in
an autocrine manner, which is inhibited in shDDX58, shIFIH1 and shMAVS CSFV
infected autophagy deficient cells. The induction of autophagy by CSFV
therefore might not only promote the clearance of damaged mitochondria but also
the decreasing transcripts of ISG via RNautophagy. <o:p></o:p></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to other positive strand RNA viruses, CSFV might also induce autophagy via the ER stress response induced by the viral NS2 and NS5A proteins which might play a role in establishing a persistent infection. In addition, the induction of NFκ-B by oxidative stress can also autophagy. If any of those pathways however contributes to viral persistence has not been investigated yet.</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhsPuEtpjYDKFySUijhlrUoMXmXJymGwlaYmXYg5wU7FRZzQkLfQeoU4UYi0-Jfv2rEGKurH2Hbe4toKA15u3BX9h8_77krzWIYiOpzYjh__BXHvMBb_nFdtjAVGefbgXd90bRxCXV0jHNw/s1600/ZIKV+CSFV+autophagy.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhsPuEtpjYDKFySUijhlrUoMXmXJymGwlaYmXYg5wU7FRZzQkLfQeoU4UYi0-Jfv2rEGKurH2Hbe4toKA15u3BX9h8_77krzWIYiOpzYjh__BXHvMBb_nFdtjAVGefbgXd90bRxCXV0jHNw/s640/ZIKV+CSFV+autophagy.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: CSFV inhibitors apoptosis and induces autophagy via multiple pathways</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Also, so far it has not been
demonstrated if CSFV induced formation of ROS also induces the induction of
TLR-9 by mitochondrial DNA. In this scenario, a complex of mtDNA and TLR-9
might be degraded via autophagy and thus abrogate antiviral signalling.</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<b style="mso-bidi-font-weight: normal;"><span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;">ZIKV and autophagy: impairment of autophagic
flux linked to ZIKV induced apoptosis ?</span></b></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In the case of ZIKV, the
formation of autophagosome like vesicles has been observed in ZIKV MR766
infected human primary fibroblasts and keratinocytes and in the cytoplasm of
C6/36 cells infected with a ZIKV isolate from a patient in Brazil although in
A549 cells infected with ZIKV H/PF/2013 no LC3 positive structures have been detected.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Following the infection
human foetal neural stem cells (fNSC) infected with either ZIKV MR766, ZIKV
H/PF/2013 or ZIKV IbH30656 the formation of neurospheres is significantly
impaired at day 7 p.i., as indicated by fewer neurospheres present which are
also smaller in size, due to the induction of apoptosis as measured by TUNEL
staining. Ina accordance with previously published results, ZIKV infected fNSC
derived neurospheres also exhibit a reduction of cell proliferation measured by
both BrdU incorporation, suggesting that ZIKV indeed does affect the
proliferation of foetal neuronal precursor cells. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to ZIKV MR766 infected human keratinocytes, the infection of
fNSC with ZIKV MR766 or ZIKV IbH30656 induces the formation of LC3-II positive
autophagosomes, without affecting autophagic flux, indicating that ZIKV
infection of fNSC induces the formation of autophagosomes without affecting the
formation of autolysosomes as measured by the degradation of p62/SQSTM-1. It
should be noted that the infection of HeLa cells transiently transfected with a
GFP/RFP-LC3 tandem plasmid with ZIKV MR766 increases GFP+/RFP+ punctae,
indicating that the formation of the autolysosome might be inhibited. The
discrepancy can either be due to the use of HeLa cells or it might be possible
that ZIKV infection leads to the proteasomal degradation of p62/SQSTM-1 in fNSC similar to DENV-2 infected Huh-7 cells. </span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;">In any case, treatment of ZIKV infected fNSC with Chloroquine decreases viral RNA/viral titres whilst Rapamycin treatment increases levels of both viral RNA and titers as
early as 10 hrs p.i. suggesting that autophagic flux is necessary for
viral replication. Based on the results described for CSFV above, autophagic
flux might be necessary to prevent viral induced apoptosis and/or antiviral
signalling; therefore, treatment with Chloroquine might prevent the degradation
of viral RNA-TLR complexes and thus induce antiviral signalling whereas in
untreated cells residual autophagy might be sufficient for inducing a partial
antiviral response.<span style="mso-spacerun: yes;"> </span>Treatment of fNSC
with 3-MA inhibits viral replication, suggesting that autophagosome formation
is required for viral replication, probably for the formation of viral RC. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;">The ability to initiate the formation of the autophagosome is further
highlighted by results that the replication of ZIKV MR766 in Atg3 -/- MEF and
Atg5 -/-/MEF as well as in MEF transfected with siATG13 or siATG3 is lower when
compared to wt MEF.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;">In DENV and HCV infected cells, the localisation of viral proteins
induces the formation of viral replication complexes by utilizing the autophagy
machinery; in a similar way, CoV nsp-3 and -4 have been shown to induce the
formation of LC3-II positive vesicles that are derived from the ER.<o:p></o:p></span><br />
<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;">In the case of ZIKV, the expression of NS4A and NS4B induces the
formation of GFP-LC3 positive punctae in HeLa-GFP-LC3 cells which is more
pronounced if both NS4A and NS4B are co-expressed. Similar to ZIKV MR766
infected cells, the co-expression of NS4A and NS4B increases the percentage of
GFP+/RFP+ positive punctae, indicating that autophagic flux might be inhibited,
although p62/SQSTM-1 levels are decreased which is probably due to proteasomal degradation of p62/SQSTM-1 (as described above). <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;">Based on immunofluorescence data and on data obtained from DENV NS4A and
DENV NS4B, both ZIKV NS4A and NS4B are localised at the ER, suggesting that
autophagy might be induced by the ER stress response.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglJYuTt1vC0TXQBIifv4fvNFrkefVQ5e5T34krkkFvgZAH7-kAZfBIMp-DL9FuVk9OwtEgBh4gTYBDYlL3R7kF9Wy6B_2TnQtoXFUu2ZbCiYuCuP_FYtT5ySSe7Dq-IiUJsNN10Yx02ZxP/s1600/ZIKV+CSFV+autophagy.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglJYuTt1vC0TXQBIifv4fvNFrkefVQ5e5T34krkkFvgZAH7-kAZfBIMp-DL9FuVk9OwtEgBh4gTYBDYlL3R7kF9Wy6B_2TnQtoXFUu2ZbCiYuCuP_FYtT5ySSe7Dq-IiUJsNN10Yx02ZxP/s640/ZIKV+CSFV+autophagy.006.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Topology of DENV NS4A and NS4B </td></tr>
</tbody></table>
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;">As described before, the ER stress response can initiate autophagy by
negatively regulating the PI-3-K/Akt pathway. Indeed, ZIKV NS4A and NS4B reduce
the phosphorylation of Akt at both Thr308 and Ser473 as well as of mTOR at
Ser2448 which can be reversed by the expression of a constitutively active form
of Akt, Myr-HA-Akt3 E17K, in ZIKV MR766 infected fNSC or HeLa cells, suggesting that NS4A and NS4B induce the ER stress response, although it has not proven experimentally yet. <o:p></o:p></span><br />
<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgJUXX6dirMzVBUX_BoQAXHRRM1Se5sFUuZFIOkQ07pujiqZWaJB41WQDEk37XINmlXbGf2YuTiCBOD63J4J8H8lFBe162KhvOmxtJcJhtHlDaMIZHAYBvIiScBKgZSTmZPARRBVsc3QJw8/s1600/ZIKV+CSFV+autophagy.005.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgJUXX6dirMzVBUX_BoQAXHRRM1Se5sFUuZFIOkQ07pujiqZWaJB41WQDEk37XINmlXbGf2YuTiCBOD63J4J8H8lFBe162KhvOmxtJcJhtHlDaMIZHAYBvIiScBKgZSTmZPARRBVsc3QJw8/s640/ZIKV+CSFV+autophagy.005.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure:ZIKV NS4A and NS4B inhibits PI3-K and therefore activates the formation of autophagosomes</td></tr>
</tbody></table>
<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-themecolor: text1;">In addition, the expression of ZIKV NS4A and NS4B decreases the
proliferation of fNSC as measured by Ki67, which is more pronounced if both
NS4A and NS4B are co-expressed. Since prolonged ER stress induces not only
autophagy but also apoptosis, the (co-) expression of NS4A and NS4B might
induce both autophagy and apoptosis although the percentage of apoptotic cells
following the transfection of fNSC with ZIKV NS4A/B has not been determined. <o:p></o:p></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjUvyO3X6rEz588JO26Aqj2uJ1nKkTgfOvb8hY609xe7oaqfs36MfL7VletBiyuqtgTLijguYySyJSnbnskWOHlbxw2vMwcnGpXOj96EMPnHFKbdRFWU8EdOPZ9uN7oc9JIv0Jcu6FDln7I/s1600/ZIKV+CSFV+autophagy.009.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjUvyO3X6rEz588JO26Aqj2uJ1nKkTgfOvb8hY609xe7oaqfs36MfL7VletBiyuqtgTLijguYySyJSnbnskWOHlbxw2vMwcnGpXOj96EMPnHFKbdRFWU8EdOPZ9uN7oc9JIv0Jcu6FDln7I/s640/ZIKV+CSFV+autophagy.009.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV NS4A and NS4B decrease the expression of Ki-67 and the proliferation of fNSC</td></tr>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-themecolor: text1;">In conclusion, the infection of fNSC with ZIKV MR766, ZIKV IbH</span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">30656 and ZIKV
H/PF/2013 induces apoptosis, decreased cell proliferation, smaller neurospheres
and the formation of autophagosomes with impaired autophagic flux, the latter
probably induced by both NS4A and NS4B protein. The notion that ZIKV MR766 inhibits
the fusion of the autophagosome with the lysosome -or lysosomal maturation- and
thus induces neurodegeneration by impairing the degradation of autophagic
substrates is supported by findings in ZIKV MR766 infected hNPC, the expression
of LAMP-2 is downregulated.</span></span><br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhaH5YySvIndiUFqib4daxr6uTkr9wdpNziczAjUWq8L8WUrmryvfnE9jncprABytLFbsoayxzHVJPBFlZCR2SiSCugF_l-RqPfBfb8Wx8jnVwbst3Yh7dmcC6cglm8HDVRvKJRGCw6XTA1/s1600/ZIKV+CSFV+autophagy.008.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhaH5YySvIndiUFqib4daxr6uTkr9wdpNziczAjUWq8L8WUrmryvfnE9jncprABytLFbsoayxzHVJPBFlZCR2SiSCugF_l-RqPfBfb8Wx8jnVwbst3Yh7dmcC6cglm8HDVRvKJRGCw6XTA1/s640/ZIKV+CSFV+autophagy.008.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV and autophagy</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"><br /></span></span></div>
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<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">If the impairment of
autophagic flux however is linked to the induction of apoptosis in ZIKV
infected primary neuronal cells has not been demonstrated. It might be possible
that similar to CSFV infected cells, autophagy is required for abrogating
antiviral signalling. <o:p></o:p></span><br />
<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">It should be noted that the infection of hNPC with ZIKV MR766 downregulates the expression of key proteins involved in the onset and progression of stress induced autophagy. Therefore, ZIKV infection of neuronal and non-neuronal cells might inhibit stress induced and selective autophagy whilst promoting the formation of viral RC. It is therefore important to analyse if the formation of viral RC is totally or only partially dependent on the ability to induce the formation of autophagosomes since viral proteins might be able to induce some of the processes required for the formation of RC independent of the autophagy machinery. </span><br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEggwx-675Gi_Ae_e26He_b_fvYx6TrYcwN8wz7PQsQPkV9n121oAXRHkFXlQVKCp67cS5ILj2gIZna7VnkdRhVv0i3z3DEz4AZYnTQiV09FhL0fbJJL6iYEzRvi-h0usPVY7SMLWxsv9ANI/s1600/ZIKV+CSFV+autophagy.007.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEggwx-675Gi_Ae_e26He_b_fvYx6TrYcwN8wz7PQsQPkV9n121oAXRHkFXlQVKCp67cS5ILj2gIZna7VnkdRhVv0i3z3DEz4AZYnTQiV09FhL0fbJJL6iYEzRvi-h0usPVY7SMLWxsv9ANI/s640/ZIKV+CSFV+autophagy.007.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table: Genes that are up- or downregulated in ZIKV MR766 infected hNPC</td></tr>
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<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">A screen of FDA approved
revealed that both Bortezomib and Ivermectin</span><span style="font-family: "helvetica";"> inhibit the replication of ZIKV Mex_1_7 in infected Huh-7, HeLa
and/or Human Amnion Epithelial Cells. Both </span></span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Bortezomib and Ivermectin
induce apoptosis of cancer cells by inhibiting autophagy, indicating that in
ZIKV infected (neuronal) cells autophagy might not only support viral
replication by forming viral RC but also by inhibiting apoptosis at least in
the early stages of viral replication. If the induction of autophagy has also
consequences for the establishment of persistently infected cells, however
remains to be seen. </span><span style="font-family: "helvetica";"><o:p></o:p></span></span></div>
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<span style="float: left; padding: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_gray.png" style="border: 0;" /></a></span>
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<u><u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Further reading </span></u></u></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Autophagy&rft_id=info%3Apmid%2F24262968&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Autophagy+enhances+the+replication+of+classical+swine+fever+virus+in+vitro.&rft.issn=1554-8627&rft.date=2014&rft.volume=10&rft.issue=1&rft.spage=93&rft.epage=110&rft.artnum=&rft.au=Pei+J&rft.au=Zhao+M&rft.au=Ye+Z&rft.au=Gou+H&rft.au=Wang+J&rft.au=Yi+L&rft.au=Dong+X&rft.au=Liu+W&rft.au=Luo+Y&rft.au=Liao+M&rft.au=Chen+J&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Pei J, Zhao M, Ye Z, Gou H, Wang J, Yi L, Dong X, Liu W, Luo Y, Liao M, & Chen J (2014). Autophagy enhances the replication of classical swine fever virus in vitro. <span style="font-style: italic;">Autophagy, 10</span> (1), 93-110 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24262968" rev="review">24262968</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Autophagy&rft_id=info%3Apmid%2F27463126&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Absence+of+autophagy+promotes+apoptosis+by+modulating+the+ROS-dependent+RLR+signaling+pathway+in+classical+swine+fever+virus-infected+cells.&rft.issn=1554-8627&rft.date=2016&rft.volume=12&rft.issue=10&rft.spage=1738&rft.epage=1758&rft.artnum=&rft.au=Pei+J&rft.au=Deng+J&rft.au=Ye+Z&rft.au=Wang+J&rft.au=Gou+H&rft.au=Liu+W&rft.au=Zhao+M&rft.au=Liao+M&rft.au=Yi+L&rft.au=Chen+J&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Pei J, Deng J, Ye Z, Wang J, Gou H, Liu W, Zhao M, Liao M, Yi L, & Chen J (2016). Absence of autophagy promotes apoptosis by modulating the ROS-dependent RLR signaling pathway in classical swine fever virus-infected cells. <span style="font-style: italic;">Autophagy, 12</span> (10), 1738-1758 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27463126" rev="review">27463126</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F9499036&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Lymphocyte+apoptosis+during+classical+swine+fever%3A+implication+of+activation-induced+cell+death.&rft.issn=0022-538X&rft.date=1998&rft.volume=72&rft.issue=3&rft.spage=1853&rft.epage=61&rft.artnum=&rft.au=Summerfield+A&rft.au=Kn%C3%B6tig+SM&rft.au=McCullough+KC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Summerfield A, Knötig SM, & McCullough KC (1998). Lymphocyte apoptosis during classical swine fever: implication of activation-induced cell death. <span style="font-style: italic;">Journal of virology, 72</span> (3), 1853-61 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/9499036" rev="review">9499036</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Autophagy&rft_id=info%3Apmid%2F27715443&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Emerging+connections+between+RNA+and+autophagy.&rft.issn=1554-8627&rft.date=2016&rft.volume=&rft.issue=&rft.spage=1&rft.epage=21&rft.artnum=&rft.au=Frankel+LB&rft.au=Lubas+M&rft.au=Lund+AH&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Frankel LB, Lubas M, & Lund AH (2016). Emerging connections between RNA and autophagy. <span style="font-style: italic;">Autophagy</span>, 1-21 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27715443" rev="review">27715443</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Virus+genes&rft_id=info%3Apmid%2F22718084&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Classical+swine+fever+virus+NS5A+protein+localizes+to+endoplasmic+reticulum+and+induces+oxidative+stress+in+vascular+endothelial+cells.&rft.issn=0920-8569&rft.date=2012&rft.volume=45&rft.issue=2&rft.spage=274&rft.epage=82&rft.artnum=&rft.au=He+L&rft.au=Zhang+YM&rft.au=Lin+Z&rft.au=Li+WW&rft.au=Wang+J&rft.au=Li+HL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">He L, Zhang YM, Lin Z, Li WW, Wang J, & Li HL (2012). Classical swine fever virus NS5A protein localizes to endoplasmic reticulum and induces oxidative stress in vascular endothelial cells. <span style="font-style: italic;">Virus genes, 45</span> (2), 274-82 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/22718084" rev="review">22718084</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=BMC+veterinary+research&rft_id=info%3Apmid%2F25439655&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Classical+swine+fever+virus+induces+oxidative+stress+in+swine+umbilical+vein+endothelial+cells.&rft.issn=&rft.date=2014&rft.volume=10&rft.issue=&rft.spage=279&rft.epage=&rft.artnum=&rft.au=He+L&rft.au=Zhang+Y&rft.au=Fang+Y&rft.au=Liang+W&rft.au=Lin+J&rft.au=Cheng+M&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">He L, Zhang Y, Fang Y, Liang W, Lin J, & Cheng M (2014). Classical swine fever virus induces oxidative stress in swine umbilical vein endothelial cells. <span style="font-style: italic;">BMC veterinary research, 10</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25439655" rev="review">25439655</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nucleic+acids+research&rft_id=info%3Apmid%2F27580721&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Molecular+signatures+associated+with+ZIKV+exposure+in+human+cortical+neural+progenitors.&rft.issn=0305-1048&rft.date=2016&rft.volume=44&rft.issue=18&rft.spage=8610&rft.epage=8620&rft.artnum=&rft.au=Zhang+F&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Cheng+Y&rft.au=Lee+EM&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Nguyen+HN&rft.au=Li+Y&rft.au=Yao+B&rft.au=Xu+M&rft.au=Xu+T&rft.au=Chen+L&rft.au=Wang+Z&rft.au=Feng+H&rft.au=Huang+WK&rft.au=Yoon+KJ&rft.au=Shan+C&rft.au=Huang+L&rft.au=Qin+Z&rft.au=Christian+KM&rft.au=Shi+PY&rft.au=Xu+M&rft.au=Xia+M&rft.au=Zheng+W&rft.au=Wu+H&rft.au=Song+H&rft.au=Tang+H&rft.au=Ming+GL&rft.au=Jin+P&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Zhang F, Hammack C, Ogden SC, Cheng Y, Lee EM, Wen Z, Qian X, Nguyen HN, Li Y, Yao B, Xu M, Xu T, Chen L, Wang Z, Feng H, Huang WK, Yoon KJ, Shan C, Huang L, Qin Z, Christian KM, Shi PY, Xu M, Xia M, Zheng W, Wu H, Song H, Tang H, Ming GL, & Jin P (2016). Molecular signatures associated with ZIKV exposure in human cortical neural progenitors. <span style="font-style: italic;">Nucleic acids research, 44</span> (18), 8610-8620 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27580721" rev="review">27580721</a></span> </span></div>
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<br />thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com2tag:blogger.com,1999:blog-8715161762555608131.post-12186840573006762302016-10-07T16:01:00.000-04:002017-01-18T15:32:56.740-05:00ZIKV and ocular infections<br />
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Although being first isolated in 1947 from a sentinel rhesus monkey in forests of Uganda, until 2007 Zika Virus (ZIKV) outbreaks have been sporadic, being limited to tropical regions in Africa as well as Southeast Asia and only been associated with relative mild symptoms in about 20% of infected people. Autochthonous transmission of ZIKV outside these areas was only reported in 2007 in the Federal States of Micronesia (FSM), 2013 in French Polynesia, and in 2015 in South America, spreading to the Caribbean and North Americas within a few months. Concomitant with the advent of ZIKV in the Americas, ZIKV was implicated in the onset of neurological diseases in foetuses, neonates and adults, namely microcephaly and Guillan-Barre Syndrome (GBS); subsequently, studies in animal models (both mice and monkeys), brain organoids, neural stem cells (NSC) and human neural progenitor cells (hNPC) confirmed that ZIKV can induce abnormal brain development probably by inducing apoptosis of neural progenitor -but not mature neurons- in a Caspase dependent pathway either in ZIKV infected cells or via bystander apoptosis of uninfected neural crest cells via inducing the secretion of cytokines. As discussed before, the infection of the vaginal mucosa might promote the transmission of ZIKV to the placenta and/or of Hofbauer cells that might cross the placenta and thus infect the embryo during the early stages of neural development, thus explaining data retroactively obtained from the 2013 ZIKV outbreak that indicated an increased risk for microcephaly of infants born to mothers that were infected with ZIKV in the first two trimesters. </span></span></div>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In addition to microcephaly however, several case reports from Brazil indicate that neonates born to ZIKV positive mothers display an array of eye malformations including blindness, intraretinal haemorrhages, chorioretinal atrophy, optic neuritis, lens sublaxation and bilateral iris colobomas, indicating that ZIKV might also affect eye development. Furthermore, in adults, ZIKV infection has been associated with conjunctivitis as well as uveitis in 10-15% of infected adults presenting themselves with ZIKV infection. Similar to EBOV, viral RNA can be detected in fluid samples taken from the anterior chamber of the eye, suggesting that ZIKV can either replicate in the eye or that ZIKV is at least present (but not necessarily replicating). ZIKV therefore joins other viruses that (potentially) can cause inflammation of the eye or blindness in neonates such as Human Cytomegalovirus (HCMV) which can be acquired both antenatal and intrapartum in addition to other viruses such as Adenovirus', Picornavirus', Herpes Simplex Virus 2 or Varicella Zoster Virus/Human Herpesvirus 3. So far however, an active eye infection as a result of ZIKV infection has not been reported to transmit to household contacts. More importantly however, the presence of viral RNA in the aqueous humor might indicate that following immunosuppression, ZIKV replication might resurface and thus might be horizontally transmitted via sexual contact or via mosquitoes and thus either sustain or restart a local. ZIKV outbreak.</span></span></div>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In order to characterize the potential of ZIKV to cause uveitis, animal models were being used. As discussed before, ZIKV does not replicate well wt C57BL/6 mice partially because the viral NS5 protein does not block mouse derived STAT2 and thus antiviral signalling. Consequently, in mice, ZIKV pathogenesis in mice is studied either in immunocompromised mice such as AG129 or Ifnar-1 -/- mice; in theory however it might also be possible to use recombinant ZIKV generated using the recently published reverse genetic systems that contain the NS5 gene of the mouse adapted ZIKV MR766 (providing that the ZIKV MR766 NS5 inhibits mouse STAT2) . In accordance with previous results which also have been discussed in previous postings, wt mice treated with Ifnar-1 -/- antibody and infected with either ZIKV H/PF/2013 or ZIKV Paraiba 2015 (isolate from Brazil) do not develop any signs of disease although high viral titres can be detected in multiple organs, including the testes of male mice, which is in contrast with Ifnar-1 -/- mice that develop severe neuroinvasive infection with decreased survival. Viral RNA in both ZIKV H/PF/2013 and ZIKV Paraiba 2015 infected mice can be detected as early as 48 hrs p.i., increasing at day 6 p.i. (H/PF/2013) and day 7 p.i. (Paraiba 2015). Also, viral RNA could be detected in tears and in lacrimal glands of ZIKV Paraiba 2015 infected mice, suggesting the presence of either infectious viral particles and/or cell debris of ZIKV infected cells due to virus induced apoptosis of infected cells. The presence of infectious ZIKV in eyes at day 7 p.i. was confirmed by infecting immunocompromised AG129 mice eye homogenates of ZIKV Paraiba 2015 infected Ifnar-1 -/- mice, whereas both tears from day 7 p.i. nor eye homogenates from day 28 p.i. contained infectious virus, indicating that tears are not infectious and that infetious virus is not present in the eye after the acute phase of the infection. In general, eye homogenates derived from mice at day 7 p.i. , caused more severe symptoms in AG129 mice compared to ZIKV Paraiba 2015 infection, especially ocular pathology and conjunctivitis, despite similar viral titres in spleen, brain and eyes, suggesting that viral particles derived from the eye might be adapted (which at this point is speculative). One possibility to investigate if ZIKV derived from eye homogenates is adapted to cells in visual system might be to infect Ifnar-1 -/- or AG129 mice with virus grown in human retinal pigment cells (ARPE-19), retinal ganglion cells or adult retinal stem cells. Nonetheless, so far sequencing eye derived virus did not reveal substitutions except an increase single mutation in the viral NS2A gene (C to T at position 3895 or A to V), but the significance of this mutation has not been evaluated. </span></span></div>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">As discussed in a previous post, the <i>in utero </i>infection of foetal mice at E4.5 via the vaginal mucosa increases the severity of foetal and neonatal brain abnormalities compared to mice infected at E8.5, confirming previous observations during the ZIKV outbreak in French Polynesia that infants born to women who got infected with ZIKV during the first trimester display a higher percentage of microcephaly. Accordingly, the offspring of Ifnar-1 -/- crossbred with Ifnar-1 +/+ mice and infected <i>in utero</i> with ZIKV Paraiba 2015 at E6.5 but not E12.5 present themselves with intrauterine growth restriction (IUGR) with foetal demise and viral RNA in the brain without any (detectable) ocular defects. Viral RNA was only detected in 2 out 41 mice infected with either ZIKV H/PF/2013 or ZIKV Paraiba 2015 at day 8 post natal (or 1 week of age), indicating that ocular defects and persistence of viral RNA in the eye is indeed a rare occurrence following infection with ZIKV <i>in utero</i>, which is supported by epidemiological findings. In contrast, the infection of 1 week old wt mice with ZIKV Paraiba 2015 not only is lethal (in accordance with findings from the early 1950s using wt mice and the primary ZIKV MR766 isolate) but also leads to high viral RNA levels in the spleen, brain and the eye concomitant with prominent Caspase-3 dependent apoptosis of cells of the optic tract, the visual cortex and the lateral geniculate nucleus as well as other components of the visual cortex, although based on the data available it is not clear if apoptosis is also induced by "bystander apoptosis" of non-infected cells in addition to ZIKV virus infected cells. Immunodeficient AG129 infected postnatally also exhibit high viral titres at day 8 p.i. in the spleen, brain and eye irrespective if the parental or a mouse-adapted ZIKV Paraiba 2015 strain is used, suggesting that the IFN response in 1 week old wt mice is unable to inhibit viral replication irrespective of the ability of ZIKV to inhibit STAT2 signalling, which might be attributed to an immature immune system. </span></span></div>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In contrast to 1 week old wt/AG129 mice, adult Ifnar-1 -/- mice infected with ZIKV Paraiba 2015 present themselves with extensive apoptosis of retinal cells in the neurosensory retina as measured using TUNEL staining that detects fragmented DNA and uveitis at day 6 p.i., accompanied by infiltration of inflammatory cells into both the anterior and posterior chambers of the eye in the absence of pan-retinal damage to the fundus. Although it is not clear how ZIKV Paraiba 2015 causes uveitis, it might be possible that the viral RNA triggers an inflammatory response that not causes localised apoptosis but also triggers the inflammation of the eye via Toll-like and/or RIG-1/MDA-5 mediated signalling pathways. In any case, viral infection is cleared by day 28 p.i.. Viral RNA can be detected in all regions of the eye between 6 and 8 days p.i. with the highest levels of viral RNA in the retinal epithelium/choroid complex, in particular bipolar and ganglion cell neurons as well as the optic nerve and cornea of ZIKV infected mice as detected by FISH and qRT-PCR, indicating that ZIKV can not infect the eye but also replicates in the eye. </span></span></div>
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<span style="-webkit-font-kerning: none; -webkit-text-stroke-color: rgb(0, 0, 0); -webkit-text-stroke-width: initial;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In conclusion, similar to other viruses such as West Nile Virus, Hepatitis C Virus or EBOV, ZIKV can infect retinal tissue, causing ocular defects in adult as well as foetal/neonate mice. So far however further studies are needed to determine if ZIKV also replicates in retinal cells, which can be done using retinal cell lines. Also, it needs to be determined if ZIKV infection of the foetal brain downregulates the expression of genes that are required for the development of the visual system; experiments can be performed either by using foetal brain of <i>in utero </i>infected mice or alternatively brain organoids and/or neural stem cells. Data previously published suggest that genes encoding for proteins that are involved in the development of the visual system are differently expressed during brain development, which might explain the greater susceptibility of foetal mice infected at E6.5. Congenital ZIKV infection therefore might therefore not only target ocular tissue but also interfere with the development of the visual system which has been suggested by recent findings using SJL mice infected with ZIKV Brazil; it should be noted however that in congenital Ifnar-1 +/- foetuses derived from C57BL/6 Ifnar-1 -/- mice, no histological abnormalities are present unless they are rare and thus were not detected due to the sample size. </span></span><span style="-webkit-text-stroke-color: rgb(0, 0, 0); -webkit-text-stroke-width: initial;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Bystander apoptosis in non ZIKV infected cells can be induced by the secretion of cytokines by ZIKV cranial neural crest cells (CNCC). In contrast to other cell types, these cells undergo only limited apoptosis upon infection with ZIKV H/PF/2013 and secrete LIF, IL-60, PAI-1, VEGF, MCSF, TNF-α and IL-17 inducing apoptosis of co-cultured neurospheres whilst preventing viral induced apoptosis of infected CNCC in a paracrine manner. Further experiments however are needed to determine if bystander apoptosis is also affecting ocular precursor cells. In a sideline, 4 week old cerebral organoids express higher levels of VEGF compared to hNPC at week 0, so that it might be possible that ZIKV infection of 4 week old cerebral organoids even further increases the expression of VEGF in CNCC and thus prevents apoptosis of CNCC via a paracrine effect. Finally, if ZIKV replicates in retinal epithelial cells, then it might inhibit STAT3 signalling and thus lead to the </span></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">degeneration of retinal epithelial cells.</span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjhRNyVw2j10jjciVwTVvPJH4fOUHp0UJHveO3D3zW6yEF86iYZyeMQ-mhYSKKdVIIVHLfHfQLqi6d8s6XeKy7YhbeBwYhWIIw1rS9ksqw7KjAXPKs5U3VJH33FBEyvBuM2HZQMkOxexoml/s1600/Untitled+2.001.jpeg" imageanchor="1" style="-webkit-text-stroke-color: rgb(0, 0, 0); -webkit-text-stroke-width: initial; font-family: Helvetica; font-size: 11px; margin-left: auto; margin-right: auto; text-align: center;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjhRNyVw2j10jjciVwTVvPJH4fOUHp0UJHveO3D3zW6yEF86iYZyeMQ-mhYSKKdVIIVHLfHfQLqi6d8s6XeKy7YhbeBwYhWIIw1rS9ksqw7KjAXPKs5U3VJH33FBEyvBuM2HZQMkOxexoml/s640/Untitled+2.001.jpeg" width="640" /></a></div>
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<tr><td class="tr-caption" style="text-align: center;">Figure: Gene groups that are upregualted in 8 week old cerebral organoids compared to 4 week old<br />
cerebral organiods</td></tr>
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<u><u><u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Further reading</span></u></u></u></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Basu, R., & Tumban, E. (2016). Zika Virus on a Spreading Spree: what we now know that was unknown in the 1950’s <span style="font-style: italic;">Virology Journal, 13</span> (1) DOI: <a href="http://dx.doi.org/10.1186/s12985-016-0623-2" rev="review">10.1186/s12985-016-0623-2</a></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=JAMA+ophthalmology&rft_id=info%3Apmid%2F27228275&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Risk+Factors+Associated+With+the+Ophthalmoscopic+Findings+Identified+in+Infants+With+Presumed+Zika+Virus+Congenital+Infection.&rft.issn=2168-6165&rft.date=2016&rft.volume=134&rft.issue=8&rft.spage=912&rft.epage=8&rft.artnum=&rft.au=Ventura+CV&rft.au=Maia+M&rft.au=Travassos+SB&rft.au=Martins+TT&rft.au=Patriota+F&rft.au=Nunes+ME&rft.au=Agra+C&rft.au=Torres+VL&rft.au=van+der+Linden+V&rft.au=Ramos+RC&rft.au=Rocha+M%C3%82&rft.au=Silva+PS&rft.au=Ventura+LO&rft.au=Belfort+R+Jr&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Ventura CV, Maia M, Travassos SB, Martins TT, Patriota F, Nunes ME, Agra C, Torres VL, van der Linden V, Ramos RC, Rocha MÂ, Silva PS, Ventura LO, & Belfort R Jr (2016). Risk Factors Associated With the Ophthalmoscopic Findings Identified in Infants With Presumed Zika Virus Congenital Infection. <span style="font-style: italic;">JAMA ophthalmology, 134</span> (8), 912-8 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27228275" rev="review">27228275</a></span> </span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+New+England+journal+of+medicine&rft_id=info%3Apmid%2F27332784&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Uveitis+Associated+with+Zika+Virus+Infection.&rft.issn=0028-4793&rft.date=2016&rft.volume=375&rft.issue=4&rft.spage=394&rft.epage=6&rft.artnum=&rft.au=Furtado+JM&rft.au=Esp%C3%B3sito+DL&rft.au=Klein+TM&rft.au=Teixeira-Pinto+T&rft.au=da+Fonseca+BA&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+New+England+journal+of+medicine&rft_id=info%3Apmid%2F27332784&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Uveitis+Associated+with+Zika+Virus+Infection.&rft.issn=0028-4793&rft.date=2016&rft.volume=375&rft.issue=4&rft.spage=394&rft.epage=6&rft.artnum=&rft.au=Furtado+JM&rft.au=Esp%C3%B3sito+DL&rft.au=Klein+TM&rft.au=Teixeira-Pinto+T&rft.au=da+Fonseca+BA&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Furtado JM, Espósito DL, Klein TM, Teixeira-Pinto T, & da Fonseca BA (2016). Uveitis Associated with Zika Virus Infection. <span style="font-style: italic;">The New England journal of medicine, 375</span> (4), 394-6 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27332784" rev="review">27332784</a></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27212660&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Targets+Human+STAT2+to+Inhibit+Type+I+Interferon+Signaling.&rft.issn=1931-3128&rft.date=2016&rft.volume=19&rft.issue=6&rft.spage=882&rft.epage=90&rft.artnum=&rft.au=Grant+A&rft.au=Ponia+SS&rft.au=Tripathi+S&rft.au=Balasubramaniam+V&rft.au=Miorin+L&rft.au=Sourisseau+M&rft.au=Schwarz+MC&rft.au=S%C3%A1nchez-Seco+MP&rft.au=Evans+MJ&rft.au=Best+SM&rft.au=Garc%C3%ADa-Sastre+A&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27212660&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Targets+Human+STAT2+to+Inhibit+Type+I+Interferon+Signaling.&rft.issn=1931-3128&rft.date=2016&rft.volume=19&rft.issue=6&rft.spage=882&rft.epage=90&rft.artnum=&rft.au=Grant+A&rft.au=Ponia+SS&rft.au=Tripathi+S&rft.au=Balasubramaniam+V&rft.au=Miorin+L&rft.au=Sourisseau+M&rft.au=Schwarz+MC&rft.au=S%C3%A1nchez-Seco+MP&rft.au=Evans+MJ&rft.au=Best+SM&rft.au=Garc%C3%ADa-Sastre+A&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Grant A, Ponia SS, Tripathi S, Balasubramaniam V, Miorin L, Sourisseau M, Schwarz MC, Sánchez-Seco MP, Evans MJ, Best SM, & García-Sastre A (2016). Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling. <span style="font-style: italic;">Cell host & microbe, 19</span> (6), 882-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27212660" rev="review">27212660</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=International+ophthalmology&rft_id=info%3Apmid%2F19711015&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Novel+infectious+agents+causing+uveitis.&rft.issn=0165-5701&rft.date=2010&rft.volume=30&rft.issue=5&rft.spage=465&rft.epage=83&rft.artnum=&rft.au=Khairallah+M&rft.au=Chee+SP&rft.au=Rathinam+SR&rft.au=Attia+S&rft.au=Nadella+V&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Khairallah M, Chee SP, Rathinam SR, Attia S, & Nadella V (2010). Novel infectious agents causing uveitis. <span style="font-style: italic;">International ophthalmology, 30</span> (5), 465-83 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/19711015" rev="review">19711015</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+%26+experimental+optometry&rft_id=info%3Apmid%2F17958570&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Occlusive+retinal+vasculitis+in+a+patient+with+West+Nile+virus.&rft.issn=0816-4622&rft.date=2007&rft.volume=90&rft.issue=6&rft.spage=463&rft.epage=7&rft.artnum=&rft.au=Teitelbaum+BA&rft.au=Newman+TL&rft.au=Tresley+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Teitelbaum BA, Newman TL, & Tresley DJ (2007). Occlusive retinal vasculitis in a patient with West Nile virus. <span style="font-style: italic;">Clinical & experimental optometry, 90</span> (6), 463-7 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/17958570" rev="review">17958570</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Stem+cells+and+development&rft_id=info%3Apmid%2F27627457&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Induced+Mortality+and+Microcephaly+in+Chicken+Embryos.&rft.issn=1547-3287&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Goodfellow+F&rft.au=Tesla+B&rft.au=Simchick+G&rft.au=Hodge+T&rft.au=Zhao+Q&rft.au=Brindley+MA&rft.au=Stice+SL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Goodfellow F, Tesla B, Simchick G, Hodge T, Zhao Q, Brindley MA, & Stice SL (2016). Zika Virus Induced Mortality and Microcephaly in Chicken Embryos. <span style="font-style: italic;">Stem cells and development</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27627457" rev="review">27627457</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+reports&rft_id=info%3Apmid%2F27612415&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infection+in+Mice+Causes+Panuveitis+with+Shedding+of+Virus+in+Tears.&rft.issn=&rft.date=2016&rft.volume=16&rft.issue=12&rft.spage=3208&rft.epage=18&rft.artnum=&rft.au=Miner+JJ&rft.au=Sene+A&rft.au=Richner+JM&rft.au=Smith+AM&rft.au=Santeford+A&rft.au=Ban+N&rft.au=Weger-Lucarelli+J&rft.au=Manzella+F&rft.au=R%C3%BCckert+C&rft.au=Govero+J&rft.au=Noguchi+KK&rft.au=Ebel+GD&rft.au=Diamond+MS&rft.au=Apte+RS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Miner JJ, Sene A, Richner JM, Smith AM, Santeford A, Ban N, Weger-Lucarelli J, Manzella F, Rückert C, Govero J, Noguchi KK, Ebel GD, Diamond MS, & Apte RS (2016). Zika Virus Infection in Mice Causes Panuveitis with Shedding of Virus in Tears. <span style="font-style: italic;">Cell reports, 16</span> (12), 3208-18 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27612415" rev="review">27612415</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+microbiology&rft_id=info%3Apmid%2F27387029&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Neuroteratogenic+Viruses+and+Lessons+for+Zika+Virus+Models.&rft.issn=0966-842X&rft.date=2016&rft.volume=24&rft.issue=8&rft.spage=622&rft.epage=36&rft.artnum=&rft.au=Kim+K&rft.au=Shresta+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Kim K, & Shresta S (2016). Neuroteratogenic Viruses and Lessons for Zika Virus Models. <span style="font-style: italic;">Trends in microbiology, 24</span> (8), 622-36 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27387029" rev="review">27387029</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27693308&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infection+Induces+Cranial+Neural+Crest+Cells+to+Produce+Cytokines+at+Levels+Detrimental+for+Neurogenesis.&rft.issn=1931-3128&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Bayless+NL&rft.au=Greenberg+RS&rft.au=Swigut+T&rft.au=Wysocka+J&rft.au=Blish+CA&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Bayless NL, Greenberg RS, Swigut T, Wysocka J, & Blish CA (2016). Zika Virus Infection Induces Cranial Neural Crest Cells to Produce Cytokines at Levels Detrimental for Neurogenesis. <span style="font-style: italic;">Cell host & microbe</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27693308" rev="review">27693308</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27162029&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Depletes+Neural+Progenitors+in+Human+Cerebral+Organoids+through+Activation+of+the+Innate+Immune+Receptor+TLR3.&rft.issn=1934-5909&rft.date=2016&rft.volume=19&rft.issue=2&rft.spage=258&rft.epage=65&rft.artnum=&rft.au=Dang+J&rft.au=Tiwari+SK&rft.au=Lichinchi+G&rft.au=Qin+Y&rft.au=Patil+VS&rft.au=Eroshkin+AM&rft.au=Rana+TM&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Dang J, Tiwari SK, Lichinchi G, Qin Y, Patil VS, Eroshkin AM, & Rana TM (2016). Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3. <span style="font-style: italic;">Cell stem cell, 19</span> (2), 258-65 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27162029" rev="review">27162029</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27453325&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Comparative+Analysis+Between+Flaviviruses+Reveals+Specific+Neural+Stem+Cell+Tropism+for+Zika+Virus+in+the+Mouse+Developing+Neocortex.&rft.issn=&rft.date=2016&rft.volume=10&rft.issue=&rft.spage=71&rft.epage=6&rft.artnum=&rft.au=Brault+JB&rft.au=Khou+C&rft.au=Basset+J&rft.au=Coquand+L&rft.au=Fraisier+V&rft.au=Frenkiel+MP&rft.au=Goud+B&rft.au=Manuguerra+JC&rft.au=Pardigon+N&rft.au=Baffet+AD&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Brault JB, Khou C, Basset J, Coquand L, Fraisier V, Frenkiel MP, Goud B, Manuguerra JC, Pardigon N, & Baffet AD (2016). Comparative Analysis Between Flaviviruses Reveals Specific Neural Stem Cell Tropism for Zika Virus in the Mouse Developing Neocortex. <span style="font-style: italic;">EBioMedicine, 10</span>, 71-6 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27453325" rev="review">27453325</a></span>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com1tag:blogger.com,1999:blog-8715161762555608131.post-77108256912637978622016-10-03T22:03:00.000-04:002016-10-05T07:32:14.863-04:00ZIKV and microcephaly: African and Asian isolates and infection of the vaginal mucosa <div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none;">
<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The recent emergence of Zika Virus
(ZIKV) in the Americas has been associated with abnormal brain development of
the foetal brain leading to microcephaly, other neurological abnormalities,
severe depilation of neonates and foetal or neonatal death. it should be noted
however that so far in the most affected countries -Brazil and Colombia- only a
subset of all reported cases of microcephaly have been shown to be tested
positive for ZIKV suggesting that other factors also may play a role in the
observed increase of microcephaly cases. Nevertheless, as discussed before,
studies in SJL mice infected with a ZIKV isolate from Brazil and from studies
using the Asian ZIKV SZ01 confirm that the ZIKV infection can indeed cause
microcephaly by inducing apoptosis of infected neural precursor cells but not
mature neuronal cells which is supported by studies using hNPC and brain
organoids. Interestingly, recent data indicate that the infection of both hNPC
and human astrocytes with ZIKV ArB41644, a strain isolated from the Central
African Republic, and ZIKV H/PF/2013, a strain isolated from French Polynesia
in 2013, show different infectivity with ZIKV H/PF/2013 exhibiting less cells
undergoing abnormal cell division as measured by CFSE positive cells using flow
cytometry at 6 days p.i. as well as less
cells displaying endoreplication/multi-nucleation and A decreased percentage of
apoptotic cells as indicated by the absence of activated Caspase-3 4 days p.i.. The absence of apoptotic cells
following the infection of neural stem cells (NSC) with ZIKV H/PF/2013 is in
stark contrast with previously discussed results which were largely obtained
from hNPC cells and brain organoids infected with ZIKV MR766 cells. Although
the reason for the observed differences is not known, it might be that ZIKV
MR766 -in contrast to ZIKV H/PF/2013- is a neurotrophic strain that has been
extensively passaged in mice brain whereas the latter is a recent isolate with
a relative low passage number and only been passaged in mosquitoe C6/36 cells
that are derived from <i>Aedes Albopictus </i> which might account for the higher percentage of apoptotic cells in hNPC infected with ZIKV MR766. If however viral induced apoptosis is also lower for ZIKV ArB41644 infected NSC cells when compared to ZIKV MR766 infected cells has not been
determined.<o:p></o:p></span></span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In addition to the observed
differences in viral titres and apoptosis, a qRT-PCR based array consisting 79
genes that are involved in antiviral signalling using mRNA collected at 4 days
p.i. from ZIKV infected NSC indicate that 19 out of 20 genes are significantly
upregulated in NSC infected with ZIKV ArB41644 but not in NSC infected with
ZIKV H/PF/2013 the exception being CXCL8. <o:p></o:p></span></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjwT0_wH34cFDqkEx3_XMIX4gJ2u3BSbMkWL6efAs89vvGTG8F2HXI1i1f9q1LYbOHEfWsikg7nIz0xRB-OxNeETxMLYzZGsNMexYboeryVtFr61EuK4TPW1ZjvM3IWrHWTw7u7gVv_PCHA/s1600/Blog+Vaginal+mucosa+ZIKV.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjwT0_wH34cFDqkEx3_XMIX4gJ2u3BSbMkWL6efAs89vvGTG8F2HXI1i1f9q1LYbOHEfWsikg7nIz0xRB-OxNeETxMLYzZGsNMexYboeryVtFr61EuK4TPW1ZjvM3IWrHWTw7u7gVv_PCHA/s640/Blog+Vaginal+mucosa+ZIKV.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table: Genes that are up-or downregulated in NSC, hNPC or organoids infected with different ZIKV isolates (nd= not determined; grey boxes= not induced)</td></tr>
</tbody></table>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Infection of NSC with ZIKV ArB41644
therefore might clear viral replication whereas the infection with ZIKV
H/PF/2013 might lead to viral persistence that might contribute to the observed
presence of ZIKV in the foetal CNS and foetal brain as well as in neonates
infected with ZIKV BR since the current strain in the Americas derived from the
Asian lineage. Unfortunately, the study did not include the original ZIKV MR766
nor an isolate from the current outbreak nor has it been established if the
infection of immunocompetent and/or immunodeficient mice with ZIKV ArB41644
increases mortality and/or abnormalities in offspring of infected mice,
although the infection of immunodeficient Ifnar1 -/- mice with ZIKV Dakar 41519
-similar to ZIKV H/PF/2013 decreases survival by 100% whereas ZIKV MR766
decreases the survival rate of infected Ifnar -/-</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">mice by 60%, whereas in wt mice, none of the
isolates tested (Dakar 41519, MR766, H/PF/2013) induces mortality if they
infected s.c. .</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">More importantly, further studies
are needed to asses if both strains from different lineages<span style="mso-spacerun: yes;"> </span>also show different transmission with regard
to the placenta and the infection of vaginal tissue such as the vaginal mucosa.
As discussed in a previous post, the infection of primary human trophoblasts
(PHTs), that prevent the infection of placental cells, with ZIKV FSS13025 (an
isolate from Cambodia propagated in C6/36 cells) induces the expression of a
variety of genes involved in antiviral signalling including a subset that are
also induced by ZIKV ArB41644 (namely, CXCL10, ISG15, OAS2, STAT1 and TLR3),
suggesting that both isolates exhibit lower viral titres due to the induction
of common antiviral signalling pathways and both might also not readily be
transmitted across the placental barrier. </span></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgB3i0zlBMQXRbLBTUOJr3ddyBBM2IZZUAnAHtm7Iue86GM0k1OEpPXxpu1H88ho6Kn620NoNtQBOcLq7krw_48OqutOj8ZbOy3pt3y33lqjsrccnD3RSurW319S7YVVBpou3QSSAzd-Nkg/s1600/Blog+Vaginal+mucosa+ZIKV.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgB3i0zlBMQXRbLBTUOJr3ddyBBM2IZZUAnAHtm7Iue86GM0k1OEpPXxpu1H88ho6Kn620NoNtQBOcLq7krw_48OqutOj8ZbOy3pt3y33lqjsrccnD3RSurW319S7YVVBpou3QSSAzd-Nkg/s640/Blog+Vaginal+mucosa+ZIKV.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table: Genes that exhibit a higher expression in primary placental cells compared to control cells </td></tr>
</tbody></table>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In contrast to both isolates from Asia and the primary isolate from Africa, ZIKV MR766 downregulates
the expression of ISG15, MyD88 and IFNAR-1 in infected hNPC (although ISG15 is
upregulated in human epithelial cells from the skin), suggesting that ZIKV
MR766 does inhibit antiviral signalling more efficiently. <o:p></o:p></span></span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Both ZIKV MR766 and a recently
isolated strain from Nicaragua, ZIKV Nica-2/16, infect and replicate in
primary human placental cells and in explants such as cytotrophoblasts,
fibroblasts, Hofbauer cells in chorionic villi, amniotic epithelial cells as
well as trophoblast progenitor cells but corresponding studies using primary or
low passage isolates from the African lineage have not been conducted so it remains to be seen if primary isolates from Africa do indeed infect vaginal and/or placental tissue and thus potentially are transmitted to the embryo and foetus. In any
case, the infection of placental cells results in high viral titres in
amniotic epithelial cells mid gestation (22.6 weeks) and lower viral titres at
late gestation (40 weeks) irrespective of the viral isolate used (MR766 or Nica-2/16), corresponding
to higher levels of Axl, TIM1 and Tyro-3 being expressed at week 22.6. <o:p></o:p></span></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg6t5zjhMH88lliU1dADpfxm53xBjuuMat3OqVCkTJSsoLiMwBlmnBx4zYnHlyrt_c2I-TV2a9-GInSjYfpPSV_Zvo7d0hgN26OO9FTVJBGNNQhHrwTdTZXrwGlQflPQNRWYd-2-ZwhjOdO/s1600/Blog+Vaginal+mucosa+ZIKV.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg6t5zjhMH88lliU1dADpfxm53xBjuuMat3OqVCkTJSsoLiMwBlmnBx4zYnHlyrt_c2I-TV2a9-GInSjYfpPSV_Zvo7d0hgN26OO9FTVJBGNNQhHrwTdTZXrwGlQflPQNRWYd-2-ZwhjOdO/s640/Blog+Vaginal+mucosa+ZIKV.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV isolates from Africa and Asia (SZ01) might induce a strong antiviral response via different pathways</td></tr>
</tbody></table>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In conclusion, it might therefore
be the case that isolates from the Asian lineage -in particular H/PF/2013- including those from the
Americas replicate efficiently in neural tissue due to failure to induce or
counteract antiviral signalling whereas (primary) isolates from the African and/or Asian lineage with the exception those related to the 2013 outbreak in French Polynesia might induce antiviral signalling and thus prevent not only persistent
infection of neural and non-neural tissue but also induce apoptosis of foetal
neural (precursor) cells, leading potentially to early miscarriage rather than persistent infection. In this context, the ZIKV MR766 isolate might be an
exception in so far as antiviral signalling is inhibited by downregulating the
expression of genes encoding for proteins involved in antiviral signalling such
as MyD88 and IFNAR-1. The inability of African isolates to counteract antiviral
signalling might explain why the outbreaks in Africa have been sporadic and low
in terms of infected individuals as well as the absence of ZIKV associated
cases of neurological infection which is a feature of the outbreak in French
Polynesia and in particular the current outbreak in the Americas. Future work
however is needed to establish if individual genes are contributing to these
differences or if the combination of viral proteins is required; here recently developed
reverse genetic systems will be of use.</span></div>
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<b><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">ZIKV and vertical
transmission: role of the vaginal mucosa</span></b></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Although the primary mode of ZIKV
transmission is via infected mosquitoes, especially <i>Aedes Agypti</i>, a
substantial number of infections are transmitted by sexual contact, with both
female to male transmission and male to female transmission as well as male to
male transmission. Indeed, following the infection with ZIKV, viral particles
can be detected in the male semen for as long as 62 days after the onset of
symptoms. ZIKV therefore joins a list of other viruses that can be transmitted
via semen for a considerable amount of time following the onset of symptoms,
with EBOV one of the most recent additions prior to the emergence of ZIKV. <o:p></o:p></span></span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">For obvious reasons, male to female
transmission poses an fictional risk factor for women who plan to become
pregnant since infection of vaginal tissues with ZIKV might also lead to the
infection of the placenta and thus the embryo during the first trimester of the
pregnancy. It is therefore of utmost importance to investigate if ZIKV not only
infects but also replicates in cells of the vaginal cells (in a similar way,
the infection of testicular cells is of importance). IFNAR-1 -/- male mice
infected with ZIKV H/PF/2013 s.c. leads to high viral tires in the brain,
spleen and testes and mating of these mice with female wt mice leads to
offspring with intrauterine growth restriction (IUGR) similar to microcephaly
in human foetuses, indicating that male to female transmission of ZIKV can
infect placental tissue and subsequently infect embryonal cells. Intravaginal
(ivag) infection of wt C57BL/6 with ZIKV FSS1305 does not decrease survival nor
weight loss of infected mice, despite viral replication in vaginal tissue from
day 1-4 p.i. with viral RNA being detectable by qRT-PCR as early as 6 hrs p.i.,
indicating that ZIKV can replicate in the vaginal mucosa of wt mice
asymptomatic. In contrast, infection of wt mice with ZIKV FSS1305 i.p. only
results in low viral titres in the spleen at 24 hrs p.i. and undetectable ZIKV
RNA at 72 hrs p.i., whilst no viral RNA can be detected in vaginal tissue,
suggesting that systemic infection does not result in ZIKV infection of the
vaginal mucosa. <o:p></o:p></span></span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to NSC, and astrocytes,
ZIKV infection of the vaginal mucosa induces the Type-I Interferon response
since female Ifnar-1 -/- mice infected ivag with ZIKV FSS1305 exhibit high
viral titres as early as 48 hrs p.i., exceeding those observed in wt mice. The
notion that ZIKV FSS1305 induces the Type-I Interferon response is supported by
that in MAVS -/- TLR-7 -/- mice ivag infection induces viral titres that are a
magnitude higher when compared to wt mice, suggesting that ZIKV primarily
induces a pathway that is dependent on IRF-3 and IRF-7 which is also supported
by results that indicate that in IRF-3 -/- IRF-7-/-/ mice, viral titres are
also significantly increased, reaching peak titres at 4-5 days p.i.. As
outlined above however, it is not clear if ZIKV FSS1305 induces the expression
of IRF-7 similar to ZIKV ArB41644 or not. Consistently, mice that have been
infected ivag do not exhibit any signs of illness, which might be important
since in women which are infected during sexual intercourse with her male
partner might exhibit an asymptomatic infection that -in the case of a
pregnancy might lead to the infection of the placenta and subsequent infection
of the embryo. <o:p></o:p></span></span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Accordingly, ivag infection of
pregnant wt mice with ZIKV FSS1305 at embryonic day E4.5 (corresponding to the
late blastocyst stage of embryonal development) or E8.5 (late
gastrulation/beginning of organogenesis) results in productive ZIKV replication
of the vaginal mucosa with the offspring of mice infected at E4.5 exhibiting a
significant growth defect despite the absence of ZIKV RNA in the placenta. This
result indicates that rather infecting placental tissue directly ZIKV might
transmitted to the embryo via Hofbauer cells or other maternal cells. In
contrast to wt mice, the placenta of Ifnar-1 -/- mice infected with ZIKV FSS1305 at E8.5 (or 10 days p.i.) exhibit high levels of ZIKV RNA that exceed those
detected in the placenta of infected IRF-3 -/- IRF-7-/-/ mice, indicating that
vaginal infection of mice with ZIKV can indeed infect the placenta although in
wt mice viral replication in the placenta might be inhibited or extremely low. <o:p></o:p></span></span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Following the infection of pregnant
wt mice with ZIKV FSS1305 at either E4.5 or E8.5, the foetal brain does contain
viral particles despite the absence of viral RNA (due to limitations of the qRT-PCR
assay used) as evidenced by positive staining for the viral NS1 protein in
neural and glial cells of the cerebellum and cortex despite normal foetal size.
These results suggest that the current assays used for detecting ZIKV
associated cases of microcephaly might not be sensitive enough to detect viral
RNA in cases of foetal deaths associated with neurological symptoms. <o:p></o:p></span></span></div>
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<span style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In summary, the male to female
transmission of ZIKV allows the replication of ZIKV in vaginal tissue and
potentially infection of embryos and thus abnormal neuronal development. Strain
specific differences might however account for the absence of microcephaly in
previous outbreaks. <o:p></o:p></span></span></div>
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Name="List Bullet 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 5"/>
<w:LsdException Locked="false" Priority="10" QFormat="true" Name="Title"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Closing"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Signature"/>
<w:LsdException Locked="false" Priority="1" SemiHidden="true"
UnhideWhenUsed="true" Name="Default Paragraph Font"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Message Header"/>
<w:LsdException Locked="false" Priority="11" QFormat="true" Name="Subtitle"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Salutation"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Date"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Heading"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Block Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Hyperlink"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="FollowedHyperlink"/>
<w:LsdException Locked="false" Priority="22" QFormat="true" Name="Strong"/>
<w:LsdException Locked="false" Priority="20" QFormat="true" Name="Emphasis"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Document Map"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Plain Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="E-mail Signature"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Top of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Bottom of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal (Web)"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Acronym"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Address"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Cite"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Code"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Definition"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Keyboard"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Preformatted"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Sample"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Typewriter"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Variable"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal Table"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="annotation subject"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="No List"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Contemporary"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Elegant"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Professional"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Balloon Text"/>
<w:LsdException Locked="false" Priority="39" Name="Table Grid"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Theme"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 9"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Placeholder Text"/>
<w:LsdException Locked="false" Priority="1" QFormat="true" Name="No Spacing"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading"/>
<w:LsdException Locked="false" Priority="61" Name="Light List"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 1"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 1"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 1"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 1"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 1"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Revision"/>
<w:LsdException Locked="false" Priority="34" QFormat="true"
Name="List Paragraph"/>
<w:LsdException Locked="false" Priority="29" QFormat="true" Name="Quote"/>
<w:LsdException Locked="false" Priority="30" QFormat="true"
Name="Intense Quote"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 1"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 1"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 1"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 1"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 1"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 1"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 1"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 2"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 2"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 2"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 2"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 2"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 2"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 2"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 2"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 2"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 2"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 2"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 3"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 3"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 3"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 3"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 3"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 3"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 3"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 3"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 3"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 3"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 3"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 3"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 3"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 4"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 4"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 4"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 4"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 4"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 4"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 4"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 4"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 4"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 4"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 4"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 4"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 4"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 4"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 5"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 5"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 5"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 5"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 5"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 5"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 5"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 5"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 5"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 5"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 5"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 5"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 5"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 5"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 6"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 6"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 6"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 6"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 6"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 6"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 6"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 6"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 6"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 6"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 6"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 6"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 6"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 6"/>
<w:LsdException Locked="false" Priority="19" QFormat="true"
Name="Subtle Emphasis"/>
<w:LsdException Locked="false" Priority="21" QFormat="true"
Name="Intense Emphasis"/>
<w:LsdException Locked="false" Priority="31" QFormat="true"
Name="Subtle Reference"/>
<w:LsdException Locked="false" Priority="32" QFormat="true"
Name="Intense Reference"/>
<w:LsdException Locked="false" Priority="33" QFormat="true" Name="Book Title"/>
<w:LsdException Locked="false" Priority="37" SemiHidden="true"
UnhideWhenUsed="true" Name="Bibliography"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="TOC Heading"/>
<w:LsdException Locked="false" Priority="41" Name="Plain Table 1"/>
<w:LsdException Locked="false" Priority="42" Name="Plain Table 2"/>
<w:LsdException Locked="false" Priority="43" Name="Plain Table 3"/>
<w:LsdException Locked="false" Priority="44" Name="Plain Table 4"/>
<w:LsdException Locked="false" Priority="45" Name="Plain Table 5"/>
<w:LsdException Locked="false" Priority="40" Name="Grid Table Light"/>
<w:LsdException Locked="false" Priority="46" Name="Grid Table 1 Light"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark"/>
<w:LsdException Locked="false" Priority="51" Name="Grid Table 6 Colorful"/>
<w:LsdException Locked="false" Priority="52" Name="Grid Table 7 Colorful"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 1"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 1"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 1"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 1"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 1"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 2"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 2"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 2"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 2"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 3"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 3"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 3"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 3"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 4"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 4"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 4"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 4"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 4"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 4"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 4"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 5"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 5"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 5"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 5"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 5"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 5"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 5"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 6"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 6"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 6"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 6"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 6"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 6"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 6"/>
<w:LsdException Locked="false" Priority="46" Name="List Table 1 Light"/>
<w:LsdException Locked="false" Priority="47" Name="List Table 2"/>
<w:LsdException Locked="false" Priority="48" Name="List Table 3"/>
<w:LsdException Locked="false" Priority="49" Name="List Table 4"/>
<w:LsdException Locked="false" Priority="50" Name="List Table 5 Dark"/>
<w:LsdException Locked="false" Priority="51" Name="List Table 6 Colorful"/>
<w:LsdException Locked="false" Priority="52" Name="List Table 7 Colorful"/>
<w:LsdException Locked="false" Priority="46"
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27688094&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Strains+Potentially+Display+Different+Infectious+Profiles+in+Human+Neural+Cells.&rft.issn=&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Simonin+Y&rft.au=Loustalot+F&rft.au=Desmetz+C&rft.au=Foulongne+V&rft.au=Constant+O&rft.au=Fournier-Wirth+C&rft.au=Leon+F&rft.au=Mol%C3%A8s+JP&rft.au=Goubaud+A&rft.au=Lemaitre+JM&rft.au=Maquart+M&rft.au=Leparc-Goffart+I&rft.au=Briant+L&rft.au=Nagot+N&rft.au=Van+de+Perre+P&rft.au=Salinas+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27688094&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Strains+Potentially+Display+Different+Infectious+Profiles+in+Human+Neural+Cells.&rft.issn=&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Simonin+Y&rft.au=Loustalot+F&rft.au=Desmetz+C&rft.au=Foulongne+V&rft.au=Constant+O&rft.au=Fournier-Wirth+C&rft.au=Leon+F&rft.au=Mol%C3%A8s+JP&rft.au=Goubaud+A&rft.au=Lemaitre+JM&rft.au=Maquart+M&rft.au=Leparc-Goffart+I&rft.au=Briant+L&rft.au=Nagot+N&rft.au=Van+de+Perre+P&rft.au=Salinas+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u>Further reading</u></span></span></div>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27688094&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Strains+Potentially+Display+Different+Infectious+Profiles+in+Human+Neural+Cells.&rft.issn=&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Simonin+Y&rft.au=Loustalot+F&rft.au=Desmetz+C&rft.au=Foulongne+V&rft.au=Constant+O&rft.au=Fournier-Wirth+C&rft.au=Leon+F&rft.au=Mol%C3%A8s+JP&rft.au=Goubaud+A&rft.au=Lemaitre+JM&rft.au=Maquart+M&rft.au=Leparc-Goffart+I&rft.au=Briant+L&rft.au=Nagot+N&rft.au=Van+de+Perre+P&rft.au=Salinas+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27688094&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Strains+Potentially+Display+Different+Infectious+Profiles+in+Human+Neural+Cells.&rft.issn=&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Simonin+Y&rft.au=Loustalot+F&rft.au=Desmetz+C&rft.au=Foulongne+V&rft.au=Constant+O&rft.au=Fournier-Wirth+C&rft.au=Leon+F&rft.au=Mol%C3%A8s+JP&rft.au=Goubaud+A&rft.au=Lemaitre+JM&rft.au=Maquart+M&rft.au=Leparc-Goffart+I&rft.au=Briant+L&rft.au=Nagot+N&rft.au=Van+de+Perre+P&rft.au=Salinas+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27688094&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Strains+Potentially+Display+Different+Infectious+Profiles+in+Human+Neural+Cells.&rft.issn=&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Simonin+Y&rft.au=Loustalot+F&rft.au=Desmetz+C&rft.au=Foulongne+V&rft.au=Constant+O&rft.au=Fournier-Wirth+C&rft.au=Leon+F&rft.au=Mol%C3%A8s+JP&rft.au=Goubaud+A&rft.au=Lemaitre+JM&rft.au=Maquart+M&rft.au=Leparc-Goffart+I&rft.au=Briant+L&rft.au=Nagot+N&rft.au=Van+de+Perre+P&rft.au=Salinas+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"></span></span><br />
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27688094&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Strains+Potentially+Display+Different+Infectious+Profiles+in+Human+Neural+Cells.&rft.issn=&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Simonin+Y&rft.au=Loustalot+F&rft.au=Desmetz+C&rft.au=Foulongne+V&rft.au=Constant+O&rft.au=Fournier-Wirth+C&rft.au=Leon+F&rft.au=Mol%C3%A8s+JP&rft.au=Goubaud+A&rft.au=Lemaitre+JM&rft.au=Maquart+M&rft.au=Leparc-Goffart+I&rft.au=Briant+L&rft.au=Nagot+N&rft.au=Van+de+Perre+P&rft.au=Salinas+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=EBioMedicine&rft_id=info%3Apmid%2F27688094&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Strains+Potentially+Display+Different+Infectious+Profiles+in+Human+Neural+Cells.&rft.issn=&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Simonin+Y&rft.au=Loustalot+F&rft.au=Desmetz+C&rft.au=Foulongne+V&rft.au=Constant+O&rft.au=Fournier-Wirth+C&rft.au=Leon+F&rft.au=Mol%C3%A8s+JP&rft.au=Goubaud+A&rft.au=Lemaitre+JM&rft.au=Maquart+M&rft.au=Leparc-Goffart+I&rft.au=Briant+L&rft.au=Nagot+N&rft.au=Van+de+Perre+P&rft.au=Salinas+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Simonin Y, Loustalot F, Desmetz C, Foulongne V, Constant O, Fournier-Wirth C, Leon F, Molès JP, Goubaud A, Lemaitre JM, Maquart M, Leparc-Goffart I, Briant L, Nagot N, Van de Perre P, & Salinas S (2016). Zika Virus Strains Potentially Display Different Infectious Profiles in Human Neural Cells. <span style="font-style: italic;">EBioMedicine</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27688094" rev="review">27688094</a></span></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> </span></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=American+journal+of+public+health&rft_id=info%3Apmid%2F26959253&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Preventing+Zika+Virus+Infections+in+Pregnant+Women%3A+An+Urgent+Public+Health+Priority.&rft.issn=0090-0036&rft.date=2016&rft.volume=106&rft.issue=4&rft.spage=589&rft.epage=90&rft.artnum=&rft.au=Bell+BP&rft.au=Boyle+CA&rft.au=Petersen+LR&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=American+journal+of+public+health&rft_id=info%3Apmid%2F26959253&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Preventing+Zika+Virus+Infections+in+Pregnant+Women%3A+An+Urgent+Public+Health+Priority.&rft.issn=0090-0036&rft.date=2016&rft.volume=106&rft.issue=4&rft.spage=589&rft.epage=90&rft.artnum=&rft.au=Bell+BP&rft.au=Boyle+CA&rft.au=Petersen+LR&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Bell BP, Boyle CA, & Petersen LR (2016). Preventing Zika Virus Infections in Pregnant Women: An Urgent Public Health Priority. <span style="font-style: italic;">American journal of public health, 106</span> (4), 589-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26959253" rev="review">26959253</a></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Lancet.+Infectious+diseases&rft_id=info%3Apmid%2F27641777&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Association+between+Zika+virus+infection+and+microcephaly+in+Brazil%2C+January+to+May%2C+2016%3A+preliminary+report+of+a+case-control+study.&rft.issn=1473-3099&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=de+Ara%C3%BAjo+TV&rft.au=Rodrigues+LC&rft.au=de+Alencar+Ximenes+RA&rft.au=de+Barros+Miranda-Filho+D&rft.au=Montarroyos+UR&rft.au=de+Melo+AP&rft.au=Valongueiro+S&rft.au=de+Albuquerque+MF&rft.au=Souza+WV&rft.au=Braga+C&rft.au=Filho+SP&rft.au=Cordeiro+MT&rft.au=Vazquez+E&rft.au=Di+Cavalcanti+Souza+Cruz+D&rft.au=Henriques+CM&rft.au=Bezerra+LC&rft.au=da+Silva+Castanha+PM&rft.au=Dhalia+R&rft.au=Marques-J%C3%BAnior+ET&rft.au=Martelli+CM&rft.au=investigators+from+the+Microcephaly+Epidemic+Research+Group&rft.au=Brazilian+Ministry+of+Health&rft.au=Pan+American+Health+Organization&rft.au=Instituto+de+Medicina+Integral+Professor+Fernando+Figueira&rft.au=State+Health+Department+of+Pernambuco&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Lancet.+Infectious+diseases&rft_id=info%3Apmid%2F27641777&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Association+between+Zika+virus+infection+and+microcephaly+in+Brazil%2C+January+to+May%2C+2016%3A+preliminary+report+of+a+case-control+study.&rft.issn=1473-3099&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=de+Ara%C3%BAjo+TV&rft.au=Rodrigues+LC&rft.au=de+Alencar+Ximenes+RA&rft.au=de+Barros+Miranda-Filho+D&rft.au=Montarroyos+UR&rft.au=de+Melo+AP&rft.au=Valongueiro+S&rft.au=de+Albuquerque+MF&rft.au=Souza+WV&rft.au=Braga+C&rft.au=Filho+SP&rft.au=Cordeiro+MT&rft.au=Vazquez+E&rft.au=Di+Cavalcanti+Souza+Cruz+D&rft.au=Henriques+CM&rft.au=Bezerra+LC&rft.au=da+Silva+Castanha+PM&rft.au=Dhalia+R&rft.au=Marques-J%C3%BAnior+ET&rft.au=Martelli+CM&rft.au=investigators+from+the+Microcephaly+Epidemic+Research+Group&rft.au=Brazilian+Ministry+of+Health&rft.au=Pan+American+Health+Organization&rft.au=Instituto+de+Medicina+Integral+Professor+Fernando+Figueira&rft.au=State+Health+Department+of+Pernambuco&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">de Araújo TV, Rodrigues LC, de Alencar Ximenes RA, de Barros Miranda-Filho D, Montarroyos UR, de Melo AP, Valongueiro S, de Albuquerque MF, Souza WV, Braga C, Filho SP, Cordeiro MT, Vazquez E, Di Cavalcanti Souza Cruz D, Henriques CM, Bezerra LC, da Silva Castanha PM, Dhalia R, Marques-Júnior ET, Martelli CM, investigators from the Microcephaly Epidemic Research Group, Brazilian Ministry of Health, Pan American Health Organization, Instituto de Medicina Integral Professor Fernando Figueira, & State Health Department of Pernambuco (2016). Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study. <span style="font-style: italic;">The Lancet. Infectious diseases</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27641777" rev="review">27641777</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27162029&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Depletes+Neural+Progenitors+in+Human+Cerebral+Organoids+through+Activation+of+the+Innate+Immune+Receptor+TLR3.&rft.issn=1934-5909&rft.date=2016&rft.volume=19&rft.issue=2&rft.spage=258&rft.epage=65&rft.artnum=&rft.au=Dang+J&rft.au=Tiwari+SK&rft.au=Lichinchi+G&rft.au=Qin+Y&rft.au=Patil+VS&rft.au=Eroshkin+AM&rft.au=Rana+TM&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">D</span><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27162029&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Depletes+Neural+Progenitors+in+Human+Cerebral+Organoids+through+Activation+of+the+Innate+Immune+Receptor+TLR3.&rft.issn=1934-5909&rft.date=2016&rft.volume=19&rft.issue=2&rft.spage=258&rft.epage=65&rft.artnum=&rft.au=Dang+J&rft.au=Tiwari+SK&rft.au=Lichinchi+G&rft.au=Qin+Y&rft.au=Patil+VS&rft.au=Eroshkin+AM&rft.au=Rana+TM&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">ang J, Tiwari SK, Lichinchi G, Qin Y, Patil VS, Eroshkin AM, & Rana TM (2016). Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3. <span style="font-style: italic;">Cell stem cell, 19</span> (2), 258-65 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27162029" rev="review">27162029</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature&rft_id=info%3Apmid%2F27279226&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+Brazilian+Zika+virus+strain+causes+birth+defects+in+experimental+models.&rft.issn=0028-0836&rft.date=2016&rft.volume=534&rft.issue=7606&rft.spage=267&rft.epage=71&rft.artnum=&rft.au=Cugola+FR&rft.au=Fernandes+IR&rft.au=Russo+FB&rft.au=Freitas+BC&rft.au=Dias+JL&rft.au=Guimar%C3%A3es+KP&rft.au=Benazzato+C&rft.au=Almeida+N&rft.au=Pignatari+GC&rft.au=Romero+S&rft.au=Polonio+CM&rft.au=Cunha+I&rft.au=Freitas+CL&rft.au=Brand%C3%A3o+WN&rft.au=Rossato+C&rft.au=Andrade+DG&rft.au=Faria+Dde+P&rft.au=Garcez+AT&rft.au=Buchpigel+CA&rft.au=Braconi+CT&rft.au=Mendes+E&rft.au=Sall+AA&rft.au=Zanotto+PM&rft.au=Peron+JP&rft.au=Muotri+AR&rft.au=Beltr%C3%A3o-Braga+PC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JL, Guimarães KP, Benazzato C, Almeida N, Pignatari GC, Romero S, Polonio CM, Cunha I, Freitas CL, Brandão WN, Rossato C, Andrade DG, Faria Dde P, Garcez AT, Buchpigel CA, Braconi CT, Mendes E, Sall AA, Zanotto PM, Peron JP, Muotri AR, & Beltrão-Braga PC (2016). The Brazilian Zika virus strain causes birth defects in experimental models. <span style="font-style: italic;">Nature, 534</span> (7606), 267-71 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27279226" rev="review">27279226</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+reports&rft_id=info%3Apmid%2F27268504&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Western+Zika+Virus+in+Human+Fetal+Neural+Progenitors+Persists+Long+Term+with+Partial+Cytopathic+and+Limited+Immunogenic+Effects.&rft.issn=&rft.date=2016&rft.volume=15&rft.issue=11&rft.spage=2315&rft.epage=22&rft.artnum=&rft.au=Hanners+NW&rft.au=Eitson+JL&rft.au=Usui+N&rft.au=Richardson+RB&rft.au=Wexler+EM&rft.au=Konopka+G&rft.au=Schoggins+JW&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Hanners NW, Eitson JL, Usui N, Richardson RB, Wexler EM, Konopka G, & Schoggins JW (2016). Western Zika Virus in Human Fetal Neural Progenitors Persists Long Term with Partial Cytopathic and Limited Immunogenic Effects. <span style="font-style: italic;">Cell reports, 15</span> (11), 2315-22 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27268504" rev="review">27268504</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27179424&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Disrupts+Neural+Progenitor+Development+and+Leads+to+Microcephaly+in+Mice.&rft.issn=1934-5909&rft.date=2016&rft.volume=19&rft.issue=1&rft.spage=120&rft.epage=6&rft.artnum=&rft.au=Li+C&rft.au=Xu+D&rft.au=Ye+Q&rft.au=Hong+S&rft.au=Jiang+Y&rft.au=Liu+X&rft.au=Zhang+N&rft.au=Shi+L&rft.au=Qin+CF&rft.au=Xu+Z&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Li C, Xu D, Ye Q, Hong S, Jiang Y, Liu X, Zhang N, Shi L, Qin CF, & Xu Z (2016). Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice. <span style="font-style: italic;">Cell stem cell, 19</span> (1), 120-6 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27179424" rev="review">27179424</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+research&rft_id=info%3Apmid%2F27174054&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Vertical+transmission+of+Zika+virus+targeting+the+radial+glial+cells+affects+cortex+development+of+offspring+mice.&rft.issn=1001-0602&rft.date=2016&rft.volume=26&rft.issue=6&rft.spage=645&rft.epage=54&rft.artnum=&rft.au=Wu+KY&rft.au=Zuo+GL&rft.au=Li+XF&rft.au=Ye+Q&rft.au=Deng+YQ&rft.au=Huang+XY&rft.au=Cao+WC&rft.au=Qin+CF&rft.au=Luo+ZG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Wu KY, Zuo GL, Li XF, Ye Q, Deng YQ, Huang XY, Cao WC, Qin CF, & Luo ZG (2016). Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice. <span style="font-style: italic;">Cell research, 26</span> (6), 645-54 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27174054" rev="review">27174054</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=JCI+insight&rft_id=info%3Apmid%2F27595140&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus+productively+infects+primary+human+placenta-specific+macrophages.&rft.issn=&rft.date=2016&rft.volume=1&rft.issue=13&rft.spage=&rft.epage=&rft.artnum=&rft.au=Jurado+KA&rft.au=Simoni+MK&rft.au=Tang+Z&rft.au=Uraki+R&rft.au=Hwang+J&rft.au=Householder+S&rft.au=Wu+M&rft.au=Lindenbach+BD&rft.au=Abrahams+VM&rft.au=Guller+S&rft.au=Fikrig+E&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Jurado KA, Simoni MK, Tang Z, Uraki R, Hwang J, Householder S, Wu M, Lindenbach BD, Abrahams VM, Guller S, & Fikrig E (2016). Zika virus productively infects primary human placenta-specific macrophages. <span style="font-style: italic;">JCI insight, 1</span> (13) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27595140" rev="review">27595140</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27247001&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Placental+Macrophages.&rft.issn=1931-3128&rft.date=2016&rft.volume=20&rft.issue=1&rft.spage=83&rft.epage=90&rft.artnum=&rft.au=Quicke+KM&rft.au=Bowen+JR&rft.au=Johnson+EL&rft.au=McDonald+CE&rft.au=Ma+H&rft.au=O%27Neal+JT&rft.au=Rajakumar+A&rft.au=Wrammert+J&rft.au=Rimawi+BH&rft.au=Pulendran+B&rft.au=Schinazi+RF&rft.au=Chakraborty+R&rft.au=Suthar+MS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Quicke KM, Bowen JR, Johnson EL, McDonald CE, Ma H, O'Neal JT, Rajakumar A, Wrammert J, Rimawi BH, Pulendran B, Schinazi RF, Chakraborty R, & Suthar MS (2016). Zika Virus Infects Human Placental Macrophages. <span style="font-style: italic;">Cell host & microbe, 20</span> (1), 83-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27247001" rev="review">27247001</a></span> </span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F27443522&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Targets+Different+Primary+Human+Placental+Cells%2C+Suggesting+Two+Routes+for+Vertical+Transmission.&rft.issn=1931-3128&rft.date=2016&rft.volume=20&rft.issue=2&rft.spage=155&rft.epage=66&rft.artnum=&rft.au=Tabata+T&rft.au=Petitt+M&rft.au=Puerta-Guardo+H&rft.au=Michlmayr+D&rft.au=Wang+C&rft.au=Fang-Hoover+J&rft.au=Harris+E&rft.au=Pereira+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Tabata T, Petitt M, Puerta-Guardo H, Michlmayr D, Wang C, Fang-Hoover J, Harris E, & Pereira L (2016). Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission. <span style="font-style: italic;">Cell host & microbe, 20</span> (2), 155-66 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27443522" rev="review">27443522</a></span></div>
thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com2tag:blogger.com,1999:blog-8715161762555608131.post-41295841288893581022016-09-14T13:49:00.002-04:002016-10-05T12:34:18.623-04:00ZIKV: antivirals and the cell cycle, TBK-1 relocalisation and immune signalling <br />
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<span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"><br /></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;"><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Zika Virus (ZIKV) is an
emerging flavivirus that was first isolated in 1947 from a sentinel</span><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;"><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"> </span><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span style="font-family: "helvetica";">monkey in
Uganda as part of study that aimed to identify novel pathogens and despite
sporadic local outbreaks in countries such as Gabon, Nigeria, Cambodia, Malaysia
and Indonesia followed by the first major outbreak in Yap/Federal States of
Micronesia 2007 </span><span style="font-family: "helvetica";"> </span><span style="font-family: "helvetica";">only caused mild disease
in humans with up to 80% of asymptomatic cases.</span></span></span></span></div>
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<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">The emergence of ZIKV
combined with severe pathogenicity following the outbreak in French Polynesia
2013/2014 with an excess of 30000 patients and particular the introduction of
ZIKV to Brazil<span style="mso-spacerun: yes;"> </span>as early as 2013 as
suggested by molecular clock analysis however raised questions about the
molecular evolution of ZIKV since ZIKV was previously only associated with
arthralgia and a mild febrile illness but not neuropathological disorders
including abnormal foetal brain development and Guillain-Barre Syndrome (GBS)
that were first identified in Pernambuco/Brazil and in a retroactive study of
the 2013 outbreak in French Polynesia. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">ZIKV is a flavivirus
closely related to Dengue Virus (DENV), Japanese Encephalitis Virus (JEV) and
Yellow Fever Virus (YFV) with a single stranded positive stranded RNA genome of
approximately 10800 bp. Similar to DENV, JEV and YFV, the ZIKV RNA encodes for
a single polyprotein that it is cleaved into the structural (Capsid (C),
pre-membrane (prM), and envelope (E)) and non-structural (NS1, NS2A, NS2B, NS3,
NS4A, 2K, NS4B, and NS5) proteins with the replication taking place in the
cytoplasm of infected although at least the C and NS5 proteins localise to the
nucleolus and to nuclear speckles respectively, suggesting that the nuclear
localisation of these proteins might be required for efficient replication of
JEV probably due to the interaction of the JEV core protein with B23, thus
relocalising B23 to the nuclear periphery. In contrast to JEV core protein
however, the DENV core protein does not co-localize with B23. In the case of
NS5, the expression of DENV NS5 interacts with components of the cellular
spliceosome –in particular with components of the U5 small nuclear
ribonucleoprotein particle- and thus disrupts the maturation of cellular pre-mRNA
by decreasing the efficiency of pre-mRNA processing, thus contributing to the
downregulation of cellular gene expression. Presently it is not known to which
extent ZIKV derived proteins interfere with these processes. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Both DENV and ZIKV NS5 have
been shown to inhibit the nuclear translocation of STAT2 and thus antiviral
signaling, suggesting that ZIKV and DENV NS5 exhibit similar if not identical
properties and similar to DENV, so called “viral factories” or viral
replication centers are formed in the cytoplasm of ZIKV infected cells which
contain both viral (progeny) RNA as well as viral proteins. Since ZIKV RC are similar
to the viral replication centers of other positive strand RNA viruses and are
positive for LC3, it has been proposed that these are formed by utilizing the
autophagic machinery although in A549 cells infected with the South Pacific
ZIKV PF-25013-18 no LC3-B positive structures have been identified (in contrast
with ZIKV 766 infected human keratinocytes or ZIKV SPH 2015 infected human astrocytes)
and chloroquine inhibits ZIKV replication in infected U87 glioblstoma cells. <o:p></o:p></span></div>
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<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In any case, as mentioned
above, both the ZIKV outbreak in French Polynesia and the current outbreak in
the Americas are are associated with neurological abnormalities, namely foetal
microcephaly/micrencephaly, lissencephaly, hydrocephaly,
cortical/periventricular calcifications, hypoplasia of the brain stem and
spinal cord, necrosis <span style="mso-spacerun: yes;"> </span>and other
congenital abnormalities such as focal pigment mottling of the retina, optic
nerve abnormalities and chorioretinal atrophy in foetuses and newborns of
previously infected women as well as uveitis, conjunctivitis and GBS in adults.
These observations suggest that ZIKV is neurotrophic, a finding which was first
reported in mice following the isolation of ZIKV from the sentinel monkey (for
further details see previous discussion here). Subsequent studies demonstrated
that ZIKV enters neuronal and non-neuronal cells via different receptors, the
phosphatidylserine TAM receptor Axl that is enriched on the surface of human glial
cells and the main receptor, and with DC-SIGN, TIM-1 and Tyro-3 as minor
receptors. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span lang="EN-US" style="font-family: "helvetica";">Consequently, recently </span><span style="font-family: "helvetica";">published studies which have been discussed</span><span style="font-family: "helvetica";"> <i style="mso-bidi-font-style: normal;"><span lang="EN-US">in extensio</span></i></span><i style="font-family: 'helvetica neue', arial, helvetica, sans-serif;"><span lang="EN-US" style="font-family: "helvetica";"> </span></i><span style="font-family: "helvetica";">before, suggest that ZIKV can infect human neural
progenitor cells (hNPC) derived from induced pluripotent stem cells, brain
organoids and neurospheres that are derived from embryonic stem cells or
induced pluripotent stem cell</span><span lang="EN-US" style="font-family: "helvetica";">s</span><span style="font-family: "helvetica";"> as well
as two foetal cell lines. </span><span lang="EN-US" style="font-family: "helvetica";">These studies showed that ZIKV induces caspase-3
dependent apoptosis which may be preceded by mitochondrial depolarization and
subsequent activation of caspase-3 via the release of cytochrome-c although the
mechanism leading to mitochondrial depolarisation has not been elucidated (see previous post for discussion)</span></span><span lang="EN-US" style="font-family: "helvetica";">. </span><span lang="EN-US" style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">ZIKV infected foetal neural tissue samples derived 13-16
weeks post conception exhibits high levels of infection in the ventricular and
subventricular zone which are positive for radial glial cells<span style="mso-spacerun: yes;"> </span>with only a small number of mature neurons
being infected and later (18 weeks pcw), suggesting that postmitotic neurons
are not susceptible to ZIKV which is confirmed by the absence of Axl in mature
neurons. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
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<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">More recent studies also
identified the vaginal mucosa and lacrimal glands of mice as being susceptible
for ZIKV thus providing a model of sexual transmission and viral persistence
respectively. Interestingly, ZIKV infection of the adult neurosensory retina
induces apoptosis as measured by TUNEL staining yet does not induce significant
pan-retinal abnormalities. <o:p></o:p></span></div>
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<b style="mso-bidi-font-weight: normal;"><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Antiviral
drugs: targeting caspase-3 <o:p></o:p></span></b></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Recently,
a drug repurposing screen identified several small molecule inhibitors that
inhibit ZIKV induced caspase-3 dependent apoptosis in ZIKV FSS 13025 (Cambodia
2010) or ZIKV MR766 (Uganda 1947) infected SNB-19 glioblastoma, human astrocytes
and hNPC. In this assay, 194 compounds were tested using two high-throughput
assays with one measuring both cell viability at 72 hrs p.i. and caspase-3/-7
activity at 6 hrs p.i. and the other measuring the caspase-3/-7 activity in a
primary screen followed secondary screen measuring both cell viability and
caspase-3/-7 activity which is then followed by tertiary screen that involves a
ZIKV replication assay, 2D & 3D neural cell models (such as hNPC and brain organoids)
and in addition measuring the effect of drug combinations on ZIKV replication
and cell viability. Despite causing apoptosis in all cell types tested, ZIKV
MR766 induced apoptosis can only be prevented by 35 compounds tested in all
cell types, with 54 inhibiting apoptosis in human astrocytes, 57 in SNB-19
glioblastoma cells and 48 in hNPC, whereas only 1 compound –a pan-caspase
inhibitor (Emericasan)- inhibiting both caspase-3/-7 activity and increasing the
viability of ZIKV MR766, ZIKV FSS 13025 and ZIKV PRVABC59 infected hNPC/SNB-19 cells
and brain organoids. In contrast to Emericasan, the vast majority of screened
not only inhibited apoptosis but also had a negative impact on cell
proliferation even in the absence of viral infection.</span><span lang="EN-US" style="font-family: "helvetica";"><o:p></o:p></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhpg28fr7XYt5aKDJyu7LwDxA9G2ubXmiFyR_2EyS0sYJsR5zscDO02pl2o16usKK3DzS7p-EBhsOPq1mksRNI2xCqwvRwdETKyN1Joi6a8oFwDQHtqnnTmNiPP0W5PJMVKo8NcPQEXPtn7/s1600/ZIKV+Antiviral+mitosis+blog.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhpg28fr7XYt5aKDJyu7LwDxA9G2ubXmiFyR_2EyS0sYJsR5zscDO02pl2o16usKK3DzS7p-EBhsOPq1mksRNI2xCqwvRwdETKyN1Joi6a8oFwDQHtqnnTmNiPP0W5PJMVKo8NcPQEXPtn7/s640/ZIKV+Antiviral+mitosis+blog.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Effect of tested compounds on cell viability of ZIKV infected cells (Astrocytes, SNB-19 glioblastoma cells<br />
and hNPC) Negative cell viablity=toxic effect even in absence of ZIKV </td></tr>
</tbody></table>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh3kY_TJ7CMhb2SVtC0QQlY0eqYnq0m6x-TzYOStOREoWij906o4GIBF2nlJJYLu2N0px5FCetBc4kzOK-oogxORlNckNXQxZEUNXkKlduldWyOSZlRmaGQPop7uE__I3Hf8ZhOHx3Ef-2w/s1600/ZIKV+Antiviral+mitosis+blog.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh3kY_TJ7CMhb2SVtC0QQlY0eqYnq0m6x-TzYOStOREoWij906o4GIBF2nlJJYLu2N0px5FCetBc4kzOK-oogxORlNckNXQxZEUNXkKlduldWyOSZlRmaGQPop7uE__I3Hf8ZhOHx3Ef-2w/s640/ZIKV+Antiviral+mitosis+blog.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Effect of tested compounds on ZIKV induced caspase-3 activity </td></tr>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Besides
preventing ZIKV induced apoptosis, Emericasan also reduced viral replication as
measured by determining viral titres and measuring the expression levels of the
viral NS1 protein, suggesting that the inhibition of cellular caspases also
inhibits viral replication. One possibility is that ZIKV induced activation of
caspase-3/-7 and/or other caspases inactivates Beclin-1 induced autophagy by
cleaving Beclin-1 at AA 133 and AA149 (TDVD133 and DQLD149 respectively) thus
not only preventing autophagy but also localising the resulting Beclin-1 C
terminal fragment to the mitochondria, inducing the release of Cytochrome-c in
addition to cleaving Phosphatidylinositol-3-Kinase (PI3KC3)/vacuolar protein
sorting complex-34 (Vps-34). Restoring Beclin-1 dependent autophagy in
Emericasan treated and ZIKV infected cells therefore might contribute to the
inhibition of viral replication. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";">Additionally,
the replication of ZIKV FSS13025 and ZIKV PRVABC59 in SNB-19 cells and human
astrocytes can be efficiently inhibited by Cyclin dependent kinase inhibitors
(Cdki) such as </span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">PHA-690509, Niclosamide<span style="mso-spacerun: yes;"> </span>and Seliciclib</span><span style="font-family: "helvetica";"> that inhibit the progression of the cell cycle,
indicating that cellular Cdk might phosphorylate the viral NS5 and/or NS5a
protein similar to the DENV-2, TBE <span style="mso-spacerun: yes;"> </span>and
YFV NS5 or BVDV NS5a or that the progression in particular from the G1 phase of
the cell cycle to S phase might be required for efficient ZIKV replication similar
to Mouse Hepatitis Virus (MHV), Infectious Bronchitis Virus (IBV), SARS-CoV and
Coxsackievirus B1. Further experiments are however needed to determine the role
of Cdk’s in ZIKV replication which might involve</span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"> using Cdk -/- MEF and/or
siRNA targeting specific Cdk. The disadvantage of using Cdki however is that
the proliferation of ZIKV PRVABC59 infected/Cdki treated cells as measured by
EdU incorporation is significantly decreased compared to non-infected hNPC at
72 hrs p.i. thus limiting the use <i style="mso-bidi-font-style: normal;">in
utero</i>. Cdki however might be useful in treating adults, preventing sexual
transmission and/or prolonged shedding of ZIKV in urine, saliva and tears. <o:p></o:p></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhhmYVhs3xYOrQnN33OSU-BOF_oETf0Ib88nQK03g9b-HxSNgPNmzgFxE9_T9p1nlu6ivveM7LLwJgJtdv0tEJ0mnAC1ETSkyjGkyPQY2ZBmXD4Dge4ybm5z1_xyoPgfmyOhPmCeWxZuflQ/s1600/ZIKV+Antiviral+mitosis+blog.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhhmYVhs3xYOrQnN33OSU-BOF_oETf0Ib88nQK03g9b-HxSNgPNmzgFxE9_T9p1nlu6ivveM7LLwJgJtdv0tEJ0mnAC1ETSkyjGkyPQY2ZBmXD4Dge4ybm5z1_xyoPgfmyOhPmCeWxZuflQ/s640/ZIKV+Antiviral+mitosis+blog.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: (A) Niclosamide: targeting viral entry (B) Cdki: targeting multiple cdk</td></tr>
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<b style="mso-bidi-font-weight: normal;"><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">ZIKV
and the cell cycle: G2 and mitotic arrest <o:p></o:p></span></b></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span lang="EN-US" style="font-family: "helvetica";"><a href="http://virologytidbits.blogspot.com/2016/05/zikv-infection-in-mice-cell-cycle.html">As
discussed</a> in a previous post, the <i style="mso-bidi-font-style: normal;">in
utero</i> infection of (mouse) foetal brains with ZIKV SZ01 decreases the
expression of proteins that previously have been linked to the development of
microcephaly, in particular those that are involved in the separation of
chromosomes during metaphase and anaphase, suggesting that ZIKV infected
embryonic and/or foetal cells might exhibit incomplete cytokinesis and
subsequent apoptosis, a notion that is supported by previous observations
that<span style="mso-spacerun: yes;"> </span>hNPC infected with ZIKV MR766 also
exhibit a decrease in the expression of the very same genes confirming that the
downregulation of genes regulating mitotic progression might arrest infected cells
in G2/M phase of the cell cycle which is confirmed by flow cytometry analysis
of infected hNPC. In addition to hNPC, more recent data indicate that the
infection of neuroepithelial cells derived from the Neocortex (NCX-NES) derived
from human specimens ranging from 5 to 8 weeks postconception with ZIKV FSS
13025 not only support viral replication as evidenced by the expression of the
viral NS1 protein but also undergo caspase-3 dependent apoptosis including
nuclear fragmentation and pyknosis as well exhibiting decreased cell
proliferation as indicated by the absence of the proliferation marker Ki-67
starting at day 3.5 p.i. and continuing until day 6.5 p.i. . In contrast to
NCX-NES cells, mature neurons do not support viral replication as measured by
the presence of NS1 probably due to the absence of the entry receptor, Axl, and
do not show a significant increase in apoptosis. Similar to the ZIKV SZ01
isolate, ZIKV FSS13025 and the ZIKV BR 243 strain (derived from the current
outbreak in Brazil) also infect radial glial cells (RGC) of the ventricular
zone (VZ), subventricular zone (SVZ) and the </span><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: 13.0pt;">intermediate zone</span></span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;"> </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">(IZ/SP), all of which
contain PCNA positive proliferating cells and VIM positive RGC cells, of <i style="mso-bidi-font-style: normal;">ex vivo</i> foetal brain slices with viral
replication being detected as early as day 3.5 p.i. , similar to NCX-NES cells.
Most interestingly however, only ZIKV infected and ZIKV NS1 positive cells exhibit
an aberrant cell morphology which indicates that primary proliferating neuronal
cells infected with an ZIKV replication competent strain (but not with an UV
inactivated strain) induce a cell cycle arrest. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
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<span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In addition to
downregulating the expression of genes related to mitotic progression such as
Aurora Kinase-B, activation of the innate immune response can induce apoptosis,
i.e. via IRF-3 mediated activation of Bax by Sendai Virus (SeV). In this case,
the dsRNA intermediate activates IPS-1 which in turn recruits TANK-binding
Kinase-1 (TBK-1) which in turn phosphorylates and activates IRF-3, the latter
binding Bax and translocating to the mitochondrion. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span lang="EN-US" style="font-family: "helvetica";">I</span><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;"><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">n the case of ZIKV
infected NCX-NES cells or foetal brain slices neither ZIKV FSS13025 nor ZIKV
PE243 increases the expression of TBK-1 but rather relocalises TBK-1 from the
centrosome to mitochondria thus potentially preventing the phosphorylation of </span><span style="font-family: "helvetica";">the centrosomal protein CEP170 and the mitotic
apparatus protein</span></span><span style="font-family: "helvetica";"> NuMA as well as </span><span style="font-family: "symbol";"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">g</span></span></span><span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">-tubulin,
leading to mitotic defects such as aberrant cytokinesis characterised by the
presence of a cleavage furrow in G1 phase of the cell cycle and/or subsequent
apoptosis due to mitotic catastrophe. The presence of cells with a cleavage
furrow might also explain the presence of a small percentage of ZIKV positive
(postmitotic) neurons. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In
addition, inhibiting the progress of mitosis, TBK-1 also might recruit IRF-3
and Bax to the mitochondria thus providing an alternative pathway culminating
in apoptosis independent of mitotic arrest. Further experiments are needed to
distinguish both pathways. Paradoxically the inhibition of TBK-1 with
inhibitors such as BX795 or Amlexanox exacerbates ZIKV induced apoptosis. One
reason might be that the relocalisation of TBK-1 in ZIKV infected cells also
induces mitophagy by recruiting p62/SQSTM-1 and/or optineurin so that treating
infected cells with TBK-1 also decreases mitophagy and thus the clearance of
damaged mitochondria. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;"><span style="font-family: "helvetica";">Besides
the induction of apoptosis, mitochondrial localisation of TBK-1 may also
interfere with immune signalling by disrupting STING mediated phosphorylation
of TBK-1 at perinuclear granulae and thus the translocation of IRF-3 to the
nucleus, thus subsequently inhibiting the Interferon response. In this context,
results from both WNV and DENV-1, -2 and -4 infected primary endothelial cells
and HEK 293T cells indicate that the viral encoded NS2A and NS4B inhibit the
phosphorylation of both TBK-1 and IRF-3 and subsequent induction of Interferon-</span><span style="font-family: "symbol"; mso-ascii-font-family: Helvetica; mso-char-type: symbol; mso-hansi-font-family: Helvetica; mso-symbol-font-family: Symbol;"><span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">beta</span></span></span><span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">, with DENV-1/-2/-4 NS4A uniquely inhibiting
TBK-1 and IKKε-directed signalling. In a similar way, PEDV has been shown to
inhibit TBK-1 signalling as well. Additionally, the expression of ZIKV NS4B
protein might –similar to to DENV NS4B- induce the elongation of mitochondria
in infected cells and disrupting the ER-Mitochondiria contact (MAM) which is
critical for immune signalling and thus abrogating the celluar RIG-1 dependent
interferon response. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjWRvCk96u0yN5tOdil7wb5cKB9hAJZqEc98KeEOcwTTnuqZXrS9WiGIhDiv00yA7aX2r4b8njgR5SCmGiDrsQE8SFB5iIRSjS6480kAOSpy_GU2lrpIHC1ESTvIXovM4CZrZHaFexSy0WI/s1600/ZIKV+Antiviral+mitosis+blog.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjWRvCk96u0yN5tOdil7wb5cKB9hAJZqEc98KeEOcwTTnuqZXrS9WiGIhDiv00yA7aX2r4b8njgR5SCmGiDrsQE8SFB5iIRSjS6480kAOSpy_GU2lrpIHC1ESTvIXovM4CZrZHaFexSy0WI/s640/ZIKV+Antiviral+mitosis+blog.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV and DENV-1/-2/-4 NS4A and TBK-1 mediated signalling:<br />
targeting phosphorylation of IRF-3</td></tr>
</tbody></table>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Apart
from inhibiting mitotic progression, interfering with TBK-1 dependent immune
signalling </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">and inducing apoptosis,
mitochondrial TBK-1 might also induce lipophagy and thus promote viral
replication by inducing mitophagy via recruitment of p62/SQSTM-1, NDP52 and/or
Optineurin. Again further studies are warranted.</span></div>
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<span style="font-size: large;"><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">In conclusion, mitotic
arrest of ZIKV infected primary neuronal cells might be caused by multiple
reason</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">s</span><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">. <a href="http://virologytidbits.blogspot.com/2016/05/zikv-infection-in-mice-cell-cycle.html">As
discussed before</a>, based on gene expression analysis of ZIKV MR766 infected
hNPC ZIKV might induce DNA replication stress that ultimately induces cell
cycle arrest and aberrant mitosis; if this cell cycle delay is preceded by a
prolonged S phase similar to IBV has not been determined. Mitotic progression</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> of ZIKV infected hNPC</span><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> might also be delayed by
downregulating components of the mitotic machinery such as Aurora-</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">A/</span><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">B</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">,
components required for chromosome segregation or the Anaphase Promoting
Complex/Cyclosome (APC/C)</span><span lang="EN-US" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">. ZIKV induced activation of autophagy might also
inhibit the onset of mitosis and thus arrest cells in G2 phase of the cell
cycle in addition to </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">inhibiting the progression
of S to G2 and/or G2 progression. Again, further studies using EdU or BrdU
incorporation to determine cell cycle progression in ZIKV infected cells are
needed (both synchronised and non-synchronised cells).</span></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhmeElHykGSNm-83iGQC0rpaReByzKthgiHuuElKxapVpD18ShkwWEg-ZcUU9HZCkwuuHlQXKGtlptEbNqGKWxC0-ViC-sHBL1XGpFPD651q4Mdn5cgOKHjje5_-iuS0v4q-gZMCeJDb4yj/s1600/ZIKV+Antiviral+mitosis+blog.005.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhmeElHykGSNm-83iGQC0rpaReByzKthgiHuuElKxapVpD18ShkwWEg-ZcUU9HZCkwuuHlQXKGtlptEbNqGKWxC0-ViC-sHBL1XGpFPD651q4Mdn5cgOKHjje5_-iuS0v4q-gZMCeJDb4yj/s640/ZIKV+Antiviral+mitosis+blog.005.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table: Genes related to mitotic progression that are up- or downregulated in ZIKV MR766 infected hNPC</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">The inhibition of viral
replication by Cdki indicates that Cdk’s are essential for viral replication
and further studies using siRNA and/or specific inhibitors should clarify the
contribution of individual Cdk such as Cdk-4/-6, Cdk-2, Cdk-3, Cdk-1 and </span><span style="font-family: "helvetica";">-</span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">since ZIKV infects neuronal cells</span><span style="font-family: "helvetica";">-</span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;"> also Cdk-5. The latter is of particular interest
since the inhibition of Cdk-5 has been shown to confer protection against
neuronal apoptosis of cerebral granule neurons and prevent </span></span><span style="font-family: "helvetica"; mso-bidi-font-weight: bold;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">aberrant S-phase entry
of postmitotic neurons. <span style="mso-spacerun: yes;"> </span></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large; mso-bidi-font-weight: bold;">In addition </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-weight: bold;">to (potentially) phosphorylating viral
proteins, Cdk might facilitate ZIKV replication indirectly by creating
favourable conditions for viral entry. In the case of DENV-2 and DENV-3, HepG2
cells have been demonstrated to be more permissive for both infection and viral
replication in G2 phase of the cell cycle compared to G1 or S phase which might
explain why the combination of Niclosamide and a Cdki increases the cell
viability of ZIKV infected human astrocytes and hNPC as well as decreasing viral
replication. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-weight: bold;">Inhibiting caspase-3 dependent apoptosis also might
prevent the cleavage of Beclin-1 and thus promote autophagy and increase cell
viability in addition in preventing mitotic entry. It is crucial therefore to
determine if caspase-3 inhibition has a negative effect on cell proliferation.
Based on the results obtained from treating ZIKV infected astrocytes with Cdki,
it may be possible that despite limiting ZIKV replication and increasing cell
viability pan-caspase inhibitors might not allow the proliferation of primary
neuronal cells infected with ZIKV. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Finally,
similar to Porcine Respiratory Syndrome Virus (PRRSV) induced apoptosis,
following the initial activation of caspase-3, the cleavage of Beclin-1 in ZIKV
infected cells might enhance mitochondrial depolarisation by releasing the
pro-apoptotic BH3 only protein Bad, followed by the localisation of Bad to the
mitochondria where it forms a dimer with the anti-apoptotic Bcl-XL thus
inactivating Bcl-XL. <span style="mso-spacerun: yes;"> </span>Since so far
cleavage of Beclin-1 in ZIKV infected cells has not been demonstrated, it
remains to be seen if this is the case or not. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjneDIxQGHAhhTCpFIR_FHA4BnWdS26wR-TC54ab5sPkQr9fqdxgC9eUhz6Tq_b98dkZARZdkSPDMl03Y-fdwUXOkcjx40N3-3GWQbAaXuZqHmjjMpPGH2-Bt5_NPWj_rP2FJhlCNTWbd_3/s1600/ZIKV+Antiviral+mitosis+blog.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjneDIxQGHAhhTCpFIR_FHA4BnWdS26wR-TC54ab5sPkQr9fqdxgC9eUhz6Tq_b98dkZARZdkSPDMl03Y-fdwUXOkcjx40N3-3GWQbAaXuZqHmjjMpPGH2-Bt5_NPWj_rP2FJhlCNTWbd_3/s640/ZIKV+Antiviral+mitosis+blog.006.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Hypothetical network of ZIKV induced changes to the cell cycle in infected cells</td></tr>
</tbody></table>
<br /></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><u>Further reading</u></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Barrows NJ, Campos RK, Powell ST, Prasanth KR, Schott-Lerner G, Soto-Acosta R, Galarza-Muñoz G, McGrath EL, Urrabaz-Garza R, Gao J, Wu P, Menon R, Saade G, Fernandez-Salas I, Rossi SL, Vasilakis N, Routh A, Bradrick SS, & Garcia-Blanco MA (2016). A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. <span style="font-style: italic;">Cell host & microbe, 20</span> (2), 259-70 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27476412" rev="review">27476412</a></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+neglected+tropical+diseases&rft_id=info%3Apmid%2F27341420&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Isolation+of+Infective+Zika+Virus+from+Urine+and+Saliva+of+Patients+in+Brazil.&rft.issn=1935-2727&rft.date=2016&rft.volume=10&rft.issue=6&rft.spage=&rft.epage=&rft.artnum=&rft.au=Bonaldo+MC&rft.au=Ribeiro+IP&rft.au=Lima+NS&rft.au=Dos+Santos+AA&rft.au=Menezes+LS&rft.au=da+Cruz+SO&rft.au=de+Mello+IS&rft.au=Furtado+ND&rft.au=de+Moura+EE&rft.au=Damasceno+L&rft.au=da+Silva+KA&rft.au=de+Castro+MG&rft.au=Gerber+AL&rft.au=de+Almeida+LG&rft.au=Louren%C3%A7o-de-Oliveira+R&rft.au=Vasconcelos+AT&rft.au=Brasil+P&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Bonaldo MC, Ribeiro IP, Lima NS, Dos Santos AA, Menezes LS, da Cruz SO, de Mello IS, Furtado ND, de Moura EE, Damasceno L, da Silva KA, de Castro MG, Gerber AL, de Almeida LG, Lourenço-de-Oliveira R, Vasconcelos AT, & Brasil P (2016). Isolation of Infective Zika Virus from Urine and Saliva of Patients in Brazil. <span style="font-style: italic;">PLoS neglected tropical diseases, 10</span> (6) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27341420" rev="review">27341420</a></span><br />
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27545505&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Neural+Progenitors+in+the+Adult+Mouse+Brain+and+Alters+Proliferation.&rft.issn=1934-5909&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Li+H&rft.au=Saucedo-Cuevas+L&rft.au=Regla-Nava+JA&rft.au=Chai+G&rft.au=Sheets+N&rft.au=Tang+W&rft.au=Terskikh+AV&rft.au=Shresta+S&rft.au=Gleeson+JG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Li H, Saucedo-Cuevas L, Regla-Nava JA, Chai G, Sheets N, Tang W, Terskikh AV, Shresta S, & Gleeson JG (2016). Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation. <span style="font-style: italic;">Cell stem cell</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27545505" rev="review">27545505</a></span><br />
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27152436&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Understanding+How+Zika+Virus+Enters+and+Infects+Neural+Target+Cells.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=559&rft.epage=60&rft.artnum=&rft.au=Miner+JJ&rft.au=Diamond+MS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Miner JJ, & Diamond MS (2016). Understanding How Zika Virus Enters and Infects Neural Target Cells. <span style="font-style: italic;">Cell stem cell, 18</span> (5), 559-60 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27152436" rev="review">27152436</a></span><br />
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+reports&rft_id=info%3Apmid%2F27612415&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infection+in+Mice+Causes+Panuveitis+with+Shedding+of+Virus+in+Tears.&rft.issn=&rft.date=2016&rft.volume=16&rft.issue=12&rft.spage=3208&rft.epage=18&rft.artnum=&rft.au=Miner+JJ&rft.au=Sene+A&rft.au=Richner+JM&rft.au=Smith+AM&rft.au=Santeford+A&rft.au=Ban+N&rft.au=Weger-Lucarelli+J&rft.au=Manzella+F&rft.au=R%C3%BCckert+C&rft.au=Govero+J&rft.au=Noguchi+KK&rft.au=Ebel+GD&rft.au=Diamond+MS&rft.au=Apte+RS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Miner JJ, Sene A, Richner JM, Smith AM, Santeford A, Ban N, Weger-Lucarelli J, Manzella F, Rückert C, Govero J, Noguchi KK, Ebel GD, Diamond MS, & Apte RS (2016). Zika Virus Infection in Mice Causes Panuveitis with Shedding of Virus in Tears. <span style="font-style: italic;">Cell reports, 16</span> (12), 3208-18 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27612415" rev="review">27612415</a></span><br />
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27038591&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Expression+Analysis+Highlights+AXL+as+a+Candidate+Zika+Virus+Entry+Receptor+in+Neural+Stem+Cells.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=591&rft.epage=6&rft.artnum=&rft.au=Nowakowski+TJ&rft.au=Pollen+AA&rft.au=Di+Lullo+E&rft.au=Sandoval-Espinosa+C&rft.au=Bershteyn+M&rft.au=Kriegstein+AR&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, & Kriegstein AR (2016). Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells. <span style="font-style: italic;">Cell stem cell, 18</span> (5), 591-6 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27038591" rev="review">27038591</a></span><br />
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Euro+surveillance+%3A+bulletin+Europeen+sur+les+maladies+transmissibles+%3D+European+communicable+disease+bulletin&rft_id=info%3Apmid%2F24626205&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus+infection+complicated+by+Guillain-Barre+syndrome--case+report%2C+French+Polynesia%2C+December+2013.&rft.issn=1025-496X&rft.date=2014&rft.volume=19&rft.issue=9&rft.spage=&rft.epage=&rft.artnum=&rft.au=Oehler+E&rft.au=Watrin+L&rft.au=Larre+P&rft.au=Leparc-Goffart+I&rft.au=Lastere+S&rft.au=Valour+F&rft.au=Baudouin+L&rft.au=Mallet+H&rft.au=Musso+D&rft.au=Ghawche+F&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastere S, Valour F, Baudouin L, Mallet H, Musso D, & Ghawche F (2014). Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013. <span style="font-style: italic;">Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin, 19</span> (9) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24626205" rev="review">24626205</a></span><br />
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Current+opinion+in+virology&rft_id=info%3Apmid%2F27179929&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+crisis+in+Brazil%3A+challenges+in+research+and+development.&rft.issn=1879-6257&rft.date=2016&rft.volume=18&rft.issue=&rft.spage=76&rft.epage=81&rft.artnum=&rft.au=Ribeiro+LS&rft.au=Marques+RE&rft.au=Jesus+AM&rft.au=Almeida+RP&rft.au=Teixeira+MM&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Ribeiro LS, Marques RE, Jesus AM, Almeida RP, & Teixeira MM (2016). Zika crisis in Brazil: challenges in research and development. <span style="font-style: italic;">Current opinion in virology, 18</span>, 76-81 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27179929" rev="review">27179929</a></span><br />
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=587&rft.epage=90&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, Yao B, Shin J, Zhang F, Lee EM, Christian KM, Didier RA, Jin P, Song H, & Ming GL (2016). Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. <span style="font-style: italic;">Cell stem cell, 18</span> (5), 587-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26952870" rev="review">26952870</a></span> </span><br />
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Virulence&rft_id=info%3Apmid%2F26670824&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Autophagy+postpones+apoptotic+cell+death+in+PRRSV+infection+through+Bad-Beclin1+interaction.&rft.issn=2150-5594&rft.date=2016&rft.volume=7&rft.issue=2&rft.spage=98&rft.epage=109&rft.artnum=&rft.au=Zhou+A&rft.au=Li+S&rft.au=Khan+FA&rft.au=Zhang+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Zhou A, Li S, Khan FA, & Zhang S (2016). Autophagy postpones apoptotic cell death in PRRSV infection through Bad-Beclin1 interaction. <span style="font-style: italic;">Virulence, 7</span> (2), 98-109 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26670824" rev="review">26670824</a></span> </span><br />
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+Communications&rft_id=info%3Adoi%2F10.1038%2Fncomms10072&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Tank+binding+kinase+1+is+a+centrosome-associated+kinase+necessary+for+microtubule+dynamics+and+mitosis&rft.issn=2041-1723&rft.date=2015&rft.volume=6&rft.issue=&rft.spage=10072&rft.epage=&rft.artnum=http%3A%2F%2Fwww.nature.com%2Fdoifinder%2F10.1038%2Fncomms10072&rft.au=Pillai%2C+S.&rft.au=Nguyen%2C+J.&rft.au=Johnson%2C+J.&rft.au=Haura%2C+E.&rft.au=Coppola%2C+D.&rft.au=Chellappan%2C+S.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Pillai, S., Nguyen, J., Johnson, J., Haura, E., Coppola, D., & Chellappan, S. (2015). Tank binding kinase 1 is a centrosome-associated kinase necessary for microtubule dynamics and mitosis <span style="font-style: italic;">Nature Communications, 6</span> DOI: <a href="http://dx.doi.org/10.1038/ncomms10072" rev="review">10.1038/ncomms10072</a></span> </span><br />
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America&rft_id=info%3Apmid%2F27035970&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Phosphorylation+of+OPTN+by+TBK1+enhances+its+binding+to+Ub+chains+and+promotes+selective+autophagy+of+damaged+mitochondria.&rft.issn=0027-8424&rft.date=2016&rft.volume=113&rft.issue=15&rft.spage=4039&rft.epage=44&rft.artnum=&rft.au=Richter+B&rft.au=Sliter+DA&rft.au=Herhaus+L&rft.au=Stolz+A&rft.au=Wang+C&rft.au=Beli+P&rft.au=Zaffagnini+G&rft.au=Wild+P&rft.au=Martens+S&rft.au=Wagner+SA&rft.au=Youle+RJ&rft.au=Dikic+I&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, Zaffagnini G, Wild P, Martens S, Wagner SA, Youle RJ, & Dikic I (2016). Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. <span style="font-style: italic;">Proceedings of the National Academy of Sciences of the United States of America, 113</span> (15), 4039-44 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27035970" rev="review">27035970</a></span> </span><br />
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+Immunology&rft_id=info%3Adoi%2F10.1038%2Fni.1800&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+TBK1+adaptor+and+autophagy+receptor+NDP52+restricts+the+proliferation+of+ubiquitin-coated+bacteria&rft.issn=1529-2908&rft.date=2009&rft.volume=10&rft.issue=11&rft.spage=1215&rft.epage=1221&rft.artnum=http%3A%2F%2Fwww.nature.com%2Fdoifinder%2F10.1038%2Fni.1800&rft.au=Thurston%2C+T.&rft.au=Ryzhakov%2C+G.&rft.au=Bloor%2C+S.&rft.au=von+Muhlinen%2C+N.&rft.au=Randow%2C+F.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Thurston, T., Ryzhakov, G., Bloor, S., von Muhlinen, N., & Randow, F. (2009). The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria <span style="font-style: italic;">Nature Immunology, 10</span> (11), 1215-1221 DOI: <a href="http://dx.doi.org/10.1038/ni.1800" rev="review">10.1038/ni.1800</a></span><br />
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<br />thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-1052835516597299732016-06-24T13:19:00.000-04:002016-06-24T13:19:44.151-04:00Flavivirus host factors: importance of the ER in viral replication<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica;"><span style="font-size: large;">With the emergence of ZIKV in
the Americas there has been a renewed interest in flaviviruses, in particular
those that are transmitted by insects which historically only generated limited
interest in the research community due to their inability to infect vertebrates
or only causing relative mild illness. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica;"><span style="font-size: large;">In recent years however, the
increase in infections caused by a number of flavivirus’ including West Nile
Virus (WNV), Yellow Fever Virus (YFV), Dengue Virus (DENV) and Zika Virus
(ZIKV) transmitted by insects such as <i style="mso-bidi-font-style: normal;">Aedes
sp</i>. and <i style="mso-bidi-font-style: normal;">Culex sp.</i> in the Pacific
islands, the Americas and more recently in Africa renewed an interest in these
viruses and the advent of new technologies allows to study the virus-host
interactions and assists in the identification of potential therapeutic
targets. <o:p></o:p></span></span></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<b style="mso-bidi-font-weight: normal;"><span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;">Flavivirus
infection and the EMC: pro-apoptotic during WNV infection whilst supporting
replication of DENV, ZIKV and YFV? <o:p></o:p></span></span></b></div>
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<br /></div>
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<span style="font-size: large;"><span style="font-family: Arial;">The Endoplasmic Reticulum (ER) membrane complex (EMC) was
originally discovered as part of a complex allowing the tethering Mitochondria to
the ER and thus facilitating the exchange of lipids between the ER and the
outer mitochondrial membrane (OMM) but later also being required for the
assembly of multipass ER membrane proteins as well as</span><span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"> the ER
associated degradation (ERAD) pathway. </span><span style="font-family: Arial;">Whilst it has been demonstrated that all EMC proteins
interact with the mitochondrial translocase of the OMM (TOM) protein 5 (TOM-5),
the role of the EMC in the assembly of proteins is less well characterised. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Arial;"><span style="font-size: large;">Genomic screens using RNAi and a CRISPR/Cas9a assay
targeting 19052 genes, the replication of both ZIKV and DENV has been shown to
depend on the presence of at least four components of the EMC, namely EMC-1,
-3, -4 and -5, suggesting that the ability of maintaining tethering
mitochondria to the ER and/or to process multipass ER membrane proteins is a
significant factor for ZIKV and DENV replication in HeLa cells and 293T cells. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Arial;"><span style="font-size: large;">Loss of EMC decreases the level of both intracellular E
protein and viral RNA as early as 40 min following the infection of HeLa cells
with either DENV-2/NGC and ZIKV MR766, similar to Axl depleted cells,
suggesting that EMC is a significant factor for viral binding and/or viral
entry, with viral entry being suggested be the limiting factor as opposed to
binding of viral particles. One mechanism might be that the loss EMC might
prevent decapsidation of the viral genome by targeting endosomes to the
lysosome and thus induce the degradation of viral RNA (see below).<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></span></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: large;"><span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";">The dependence of ZIKV and DENV on the
integrity of the EMC therefore might extend beyond facilitating viral entry to
the formation of the viral replication centre as well as the release of viral
particles via COPII independent pathways similar to Mouse Hepatitis Virus.
Further studies using the DENV and ZIKV replicon systems are however needed to
characterize the role of EMC in viral replication and release as well in initiating
the ERAD response. In the case of WNV, the expression of seven genes –including
EMC-2 and -3- has been shown to be crucial to WNV induced cell death in HeLa
and 293FT cells via the ERAD pathway whereas in DENV-NGC1 and various ZIKV
strains (MR766, PR 2015 and Cambodia) infected HeLa cells the knockout of EMC-1,
-2, -4, or-5 reduces viral replication, suggesting that the EMC supports viral
replication as determined by intracellular staining for the viral E protein at
48 hrs p.i. . Closer examination suggests that in addition to a potential role
of EMC in the formation of viral RC and/or transport of viral particles to the
cell surface, EMC has also a role in viral entry, specifically after viral
binding but prior to viral endocytosis. Although the role of the EMC is only
poorly characterized, it might be possible that the knockout of EMC might
promote the degradation of viral particles and/or the RC by targeting viral RC
(and late endosomes containing viral particles following viral entry) to
lysosomes and thus promote the degradation rather than release of mature viral
particles. This hypothesis is supported by findings that the position and
timing of endosome fission is dependent on the ER contact site. In Cos-7 cells
expressing mCherry-Rab7 (a marker for late endosomes) and GFP-</span><span style="font-family: 'Times New Roman';"> </span><span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";">Sec61β (a
marker for the ER), a small cargo containing Rab7<sup>+</sup> compartment buds
from a larger vacuolar Rab7<sup>+</sup> compartment with an ER tubule localised
perpendicular to the fission site that “cups” the bud just prior fission.
Closer examination of these sites revealed that prior fission components of the
retromer complex including FAM21 (which is involved in endosomal sorting)
co-localise to the site of fission, indicating that the localization of
proteins to the fission site determines the sorting of cargo. Future work
however is needed to determine the role of the EMC in the sorting of endosomes
and the role of EMC during the formation of viral RC; thus any role of EMC in
the role of the development of ZIKV and DENV RC is hypothetical. <o:p></o:p></span></span></div>
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<br /></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;">An additional role for EMC in the
replication of both ZIKV and DENV might the recruitment of mitochondria and
thus the facilitation of lipophagy. The transfer of phospholipids from the ER
to Mitochondria is believed to be non-vesicular and to occur at sites of close contact
between the ER and Mitochondria. In <i style="mso-bidi-font-style: normal;">S. cerevisiae</i>,
deletion of EMC components leads to a decreased transfer of phosphatidylserine
(PS) from the ER to Mitochondria which as a consequence contain decreased
levels of both PS and Phosphatidyletholamine (PE), thus leading to decreased
cell growth.<span style="mso-spacerun: yes;"> </span>Since both PS and PE are
also involved in the formation of lipid droplets (LD), EMC deficiency might
also impact viral replication by decreased formation of LD and thus decreased
lipophagy. Again, more research is needed to verify the involvement of EMC in
LD synthesis during ZIKV and DENV infection. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;">In the case of WNV, the deletion of
EMC-2 partially prevents WNV induced apoptosis, indicating that EMC-2 is a
factor for viral induced apoptosis. Besides the potential involvement of ERAD
in WNV induced apoptosis not much is known and indeed speculative. One possible
mechanism is that viral proteins associate with EMC-2 and thus increase ER
stress, inducing ERAD and apoptosis due to lipid depletion. On the other hand,
deletion of EMC-2 mitigates WNV induced apoptosis. It might be necessary
therefore to monitor the ER stress response in WNV infected EMC-2<sup>-/- <span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span></sup>cells
by artificially inducing the accumulation of unfolded proteins in the ER. <o:p></o:p></span></span></div>
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<br /></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;">The importance for the ER for ZIKV
replication is further strengthened by observations that in cells infected with
various members of the <i style="mso-bidi-font-style: normal;">Flaviviridae </i>–including
but not limited to WNV, DENV, YFV, and Japanese Encephalitis Virus (JEV)- viral
proteins are localised to the ER and indeed viral proteins are processed at the
ER prior viral assembly. As has been discussed in prior posts, the localisation
of viral proteins from JEV at the ER induces the ER stress response concomitant
with the formation of autophagosomes and ZIKV infection of primary human
fibroblasts has been associated with an increase in autophagosomes. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;">The role of the ER in the replication
of Flavivirus’ has been further supported by recent findings that the expression
of sgRNAs related to the ERAD response (including EMC-4 and -6), ER
translocation machinery or the Oligosaccharyl transferase complex (OST)
decreases the replication of WNV (Kunjin), ZIKV H/PF/2013, YFV (12D vaccine
strain), JEV and DENV-2 in 293T cells as well as in a Drosophila cell line,
DL-1. Two of the genes tested encode for two of the five components of the
cellular Signal Peptidase Complex (SPC), namely SPCS-1 and SPCS-3. Indeed, WNV,
JEV, DENV and ZIKV do not replicate in SPCS-1<sup>-/-<span style="mso-spacerun: yes;"> </span></sup>293T and SPCS-1<sup>-/-<span style="mso-spacerun: yes;"> </span></sup>Huh 7.5 cells and both WNV and DENV-2
are not replicating in U2OS cells transfected with either siRNA targeting
SPCS-1 or SPCS-3, suggesting that viral polyprotein consisting of the
structural and non-structural proteins requires to be processed at the ER by
SPCS-1 and/or SPCS-3.</span><o:p></o:p></span></div>
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<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFYjPN-ayRoFKOUwDP1iMWXwBG5YY3ulLdGqEWPcvglqMx0f5deKwhW0ShHSt6ZU5DlyI6XS11C98A5G2BfP0vBpV9X9KWiYcR2slCo1zuscBJHuhzMTjkRwdv9WjS4d8fty5hTOgXIsVB/s1600/Flavivirus+and+ER-+EMC+and+SPCS-1.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFYjPN-ayRoFKOUwDP1iMWXwBG5YY3ulLdGqEWPcvglqMx0f5deKwhW0ShHSt6ZU5DlyI6XS11C98A5G2BfP0vBpV9X9KWiYcR2slCo1zuscBJHuhzMTjkRwdv9WjS4d8fty5hTOgXIsVB/s640/Flavivirus+and+ER-+EMC+and+SPCS-1.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Prototype Flavivirus genome</td></tr>
</tbody></table>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: large;"><span style="font-family: Helvetica;">This notion is supported by results
showing that in SPCS-1</span><sup style="font-family: Helvetica;">-/- </sup><span style="font-family: Helvetica;">293T
cells infected with WNV the levels of both the viral prM and E protein are
reduced at 12 hrs p.i. and non-cleaved prM, E proteins are detectable at 24 hrs
p.i., whereas cleavage of the viral C protein in SPCS-1</span><sup style="font-family: Helvetica;">-/- </sup><span style="font-family: Helvetica;">293T cells is not affected with similar
finding in cells transfected with a prM-E-C plasmid, indicating therefore that
the cellular Signal Peptidase complex is required for the cleavage of prM and E
(but not C). Further experiments revealed that the leader sequence preceding
the viral E protein however is not cleaved by SPCS (in contrast to the leader
sequence preceding prM), suggesting that the cleavage of prM is necessary for
the processing of E in a sequential manner. In a similar way the processing of
the viral NS1 protein depends on the previous processing of prM but itself is
not dependent processed by SPCS-1.</span></span></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;">In line with these results, the loss of
EMC might induce the accumulation of misfolded viral proteins and/or decreased
incorporation of viral proteins into the ER and thus decrease viral
replication. </span><o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjNpNud-OoJ1rtZ6mcUWtyI3OSu_COA2CRX82WMItnhRqlZvJ4biXXejrhk8KopaVtDYMsBuP5qn92HdvMH9umowfCx9QP11EAc0nwVVupK7keAnx5u68VEZtcHngbqBCz2PC0dZi6PLlHe/s1600/Flavivirus+and+ER-+EMC+and+SPCS-1.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjNpNud-OoJ1rtZ6mcUWtyI3OSu_COA2CRX82WMItnhRqlZvJ4biXXejrhk8KopaVtDYMsBuP5qn92HdvMH9umowfCx9QP11EAc0nwVVupK7keAnx5u68VEZtcHngbqBCz2PC0dZi6PLlHe/s640/Flavivirus+and+ER-+EMC+and+SPCS-1.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Localisation of the signal sequence of prM in the context of structural and non-structural protein<br />localisation in the ER </td></tr>
</tbody></table>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-size: large;"><span style="font-family: Helvetica;">In
conclusion, the ER -in particular the EMC and Signal Peptidase Complex- plays a
pivotal role in the replication of ZIKV and DENV. Whilst the connection between
the EMC and viral replication is still obscure, the role of ER localised
cellular signal peptidases is better characterized (at least for WNV) although
questions remain, in particular if the cleavage of prM leader sequence induces
a structural change that increases the stability of E which would be consistent
with a chaperone-like role for prM in the folding of E in cells infected with
Tick Borne Encephalitis Virus and evidenced by lower expression levels of both
prM and E in SPCS-1</span><sup style="font-family: Helvetica;">-/- </sup><span style="font-family: Helvetica;">293T
cells expressing prM and E derived from WNV</span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="color: black; font-family: Helvetica; mso-bidi-font-family: "Times New Roman"; mso-themecolor: text1;"><span style="font-size: large;">compared
to wt cells. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="color: black; font-family: Helvetica; mso-bidi-font-family: "Times New Roman"; mso-themecolor: text1;"><span style="font-size: large;">In
addition to EMC and SPCS-1/-3, the genome wide CRISPR/Cas9a assay based screen
identified other ER resident proteins that are required for viral replication,
including components of OST and the ER translocation machinery such as OST-C
and Sec61β whose contribution to viral replication is still undetermined.<span style="mso-spacerun: yes;"> </span></span><o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="color: black; font-family: Helvetica; mso-bidi-font-family: "Times New Roman"; mso-themecolor: text1;"><span style="font-size: large;">It
might be also of interest to explore the question if </span></span><span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;">prM
co-localises and/or interact directly with SPSC-1 or other components of Signal
Peptidase complex? As mentioned above, the absence of the EMC might induce the
relocalisation of endosomes to lysosomes and thus affect sorting. One of the
questions to be answered therefore is if the absence of the EMC -or components
of the EMC- induces the localisation of viral RC to lysosomes and thus prevents
the release of viral particles. Further studies are needed to address these and
other questions. </span><o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;"><br /></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;"><u>Further reading</u></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica; mso-bidi-font-family: "Times New Roman";"><span style="font-size: large;"><u><br /></u></span></span></div>
<div style="-webkit-text-stroke-color: rgb(0, 0, 0); -webkit-text-stroke-width: initial; line-height: normal; min-height: 14px; text-align: justify;">
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span style="-webkit-font-kerning: none;"></span><br /></span></div>
<div style="-webkit-text-stroke-color: rgb(0, 0, 0); -webkit-text-stroke-width: initial; line-height: normal; text-align: justify;">
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span style="font-kerning: none;">Savidis G., et al.(2016) </span><span style="-webkit-font-kerning: none; -webkit-text-stroke-width: initial;">“Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics” </span><span style="-webkit-font-kerning: none; -webkit-text-stroke-width: initial; text-decoration: underline;">Cell Reports</span><span style="-webkit-font-kerning: none; -webkit-text-stroke-width: initial;"> 16, 1–15</span></span></div>
<div style="-webkit-text-stroke-color: rgb(0, 0, 0); -webkit-text-stroke-width: initial; line-height: normal; text-align: justify;">
<span style="font-kerning: none;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><br /></span></span></div>
<div style="-webkit-text-stroke-color: rgb(0, 0, 0); -webkit-text-stroke-width: initial; line-height: normal; text-align: justify;">
<span style="font-kerning: none;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Zhang, et al. (2016) </span></span><span style="-webkit-text-stroke-width: initial; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">“A CRISPR screen defines a signal peptide processing pathway required by flaviviruses”</span><span style="-webkit-text-stroke-width: initial; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;"> </span></div>
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Name="toa heading"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Bullet 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Number 5"/>
<w:LsdException Locked="false" Priority="10" QFormat="true" Name="Title"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Closing"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Signature"/>
<w:LsdException Locked="false" Priority="1" SemiHidden="true"
UnhideWhenUsed="true" Name="Default Paragraph Font"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="List Continue 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Message Header"/>
<w:LsdException Locked="false" Priority="11" QFormat="true" Name="Subtitle"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Salutation"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Date"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Heading"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Block Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Hyperlink"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="FollowedHyperlink"/>
<w:LsdException Locked="false" Priority="22" QFormat="true" Name="Strong"/>
<w:LsdException Locked="false" Priority="20" QFormat="true" Name="Emphasis"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Document Map"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Plain Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="E-mail Signature"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Top of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Bottom of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal (Web)"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Acronym"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Address"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Cite"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Code"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Definition"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Keyboard"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Preformatted"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Sample"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Typewriter"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Variable"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal Table"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="annotation subject"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="No List"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Contemporary"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Elegant"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Professional"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Balloon Text"/>
<w:LsdException Locked="false" Priority="39" Name="Table Grid"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Theme"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 9"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Placeholder Text"/>
<w:LsdException Locked="false" Priority="1" QFormat="true" Name="No Spacing"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading"/>
<w:LsdException Locked="false" Priority="61" Name="Light List"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 1"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 1"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 1"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 1"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 1"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Revision"/>
<w:LsdException Locked="false" Priority="34" QFormat="true"
Name="List Paragraph"/>
<w:LsdException Locked="false" Priority="29" QFormat="true" Name="Quote"/>
<w:LsdException Locked="false" Priority="30" QFormat="true"
Name="Intense Quote"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 1"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 1"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 1"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 1"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 1"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 1"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 1"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 2"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 2"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 2"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 2"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 2"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 2"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 2"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 2"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 2"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 2"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 2"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 3"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 3"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 3"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 3"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 3"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 3"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 3"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 3"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 3"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 3"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 3"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 3"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 3"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 4"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 4"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 4"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 4"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 4"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 4"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 4"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 4"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 4"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 4"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 4"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 4"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 4"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 4"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 5"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 5"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 5"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 5"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 5"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 5"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 5"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 5"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 5"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 5"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 5"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 5"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 5"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 5"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 6"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 6"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 6"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 6"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 6"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 6"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 6"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 6"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 6"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 6"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 6"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 6"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 6"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 6"/>
<w:LsdException Locked="false" Priority="19" QFormat="true"
Name="Subtle Emphasis"/>
<w:LsdException Locked="false" Priority="21" QFormat="true"
Name="Intense Emphasis"/>
<w:LsdException Locked="false" Priority="31" QFormat="true"
Name="Subtle Reference"/>
<w:LsdException Locked="false" Priority="32" QFormat="true"
Name="Intense Reference"/>
<w:LsdException Locked="false" Priority="33" QFormat="true" Name="Book Title"/>
<w:LsdException Locked="false" Priority="37" SemiHidden="true"
UnhideWhenUsed="true" Name="Bibliography"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="TOC Heading"/>
<w:LsdException Locked="false" Priority="41" Name="Plain Table 1"/>
<w:LsdException Locked="false" Priority="42" Name="Plain Table 2"/>
<w:LsdException Locked="false" Priority="43" Name="Plain Table 3"/>
<w:LsdException Locked="false" Priority="44" Name="Plain Table 4"/>
<w:LsdException Locked="false" Priority="45" Name="Plain Table 5"/>
<w:LsdException Locked="false" Priority="40" Name="Grid Table Light"/>
<w:LsdException Locked="false" Priority="46" Name="Grid Table 1 Light"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark"/>
<w:LsdException Locked="false" Priority="51" Name="Grid Table 6 Colorful"/>
<w:LsdException Locked="false" Priority="52" Name="Grid Table 7 Colorful"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 1"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 1"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 1"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 1"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 1"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 2"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 2"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 2"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 2"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 3"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 3"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 3"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 3"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 4"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 4"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 4"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 4"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 4"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 4"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 4"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 5"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 5"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 5"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 5"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 5"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 5"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 5"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 6"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 6"/>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com1tag:blogger.com,1999:blog-8715161762555608131.post-14550458879885127642016-06-10T13:51:00.000-04:002016-06-10T13:51:45.787-04:00Yellow fever virus in Africa: current situation and importance <div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Yellow haemorraghic fever (YF) is caused
by Yellow Fever Virus (YFV), a prototype Flavivirus and as such as related to
Japanese Encephalitis Virus (JEV), Dengue Virus (DENV) and Zika Virus (ZIKV).
Similar to DENV and ZIKV, YFV is transmitted by <i>Aedes agypti</i> both in Africa and South America and clinical
manifestations range from asymptomatic infections to multi organ failure and
subsequent death. In the case of symptomatic infections, most cases are
self-limiting with a febrile illness lasting for about four days that
associated with myalgia, prostration and back pain which is accompanied with
high viraemia and increased risk for mosquitoe infection during a blood meal.
15-25% of infected patients however enter a period of “intoxication” following
the remission of fever, multi-organ disease involving failure of the liver and
kidneys, jaundice and an unusual susceptibility haemorrhage due to coagulation
defects (bleeding diathesis), resulting in the death of 20-50% of affected
patients. <o:p></o:p></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">YF was initially confined to Africa but
entered South America together with infected <i style="mso-bidi-font-style: normal;">Ae. Agypti</i> with the crowded conditions on slave ships supported and
sustained the introduction of YFV into South America. Following the arrival in
the slave port cities, the surrounding forests became the breeding ground of <i style="mso-bidi-font-style: normal;">Ae. Agypti</i> for centuries to come.
Similar to ZIKV, YFV is an enzootic virus, maintained in sylvatic transmission
cycles between monkeys and mosquitoes only causing sporadic outbreaks in human
–particularly urban-populations. In both Africa and South America, mosquitoe
populations reach high densities during the “wet” (rainy) season of the year
and thus increase risk of human infections by either occupational or
recreational exposure thus causing relative small outbreaks that are
self-limiting. Larger outbreaks however become more common in areas where
larger human and vector populations overlap and thus allow for human to human
transmission and spread to previously uninfected areas by travel. Indeed, YFV
epidemics were reported as far north as Philadelphia as late as the 18<sup>th</sup>
century due to travel. Following the development and introduction of the Yellow
Fever vaccine and mass mosquitoe extermination campaigns in the mid-20<sup>th</sup>
century, despite a brief resurgence, epidemic YF has been almost eradicated
from the Americas, with local outbreaks associated with forest exposure.
However the appearance of Chikungunya Virus<span style="mso-spacerun: yes;">
</span>(CHIKV), DENV and most recently ZIKV, suggests that the failure of sustained
vector control and YFV vaccination might lead to a resurgence of YFV as well. <o:p></o:p></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">In contrast to the Americas, in Africa
150 YF outbreaks in 26 countries with 200000 cases annually were recorded
between 1980 and 2012 by the WHO. Vaccination campaigns however resulted in a
57% decrease of cases in targeted countries. <o:p></o:p></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGxTxmiBGGpDNNa_ycL-JzueYj0ZPEXDKwEPsKfIOvHEOWp4aYvCd6GkBMP0H40zWyAb9JEuw-aiPPr7c1HvoAYlUPvtZui28kEmUbjlDkmV3aOjx0btB0GkZUwql9_PXr8wNrkjdJnDWv/s1600/YFV+in+Angola.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGxTxmiBGGpDNNa_ycL-JzueYj0ZPEXDKwEPsKfIOvHEOWp4aYvCd6GkBMP0H40zWyAb9JEuw-aiPPr7c1HvoAYlUPvtZui28kEmUbjlDkmV3aOjx0btB0GkZUwql9_PXr8wNrkjdJnDWv/s640/YFV+in+Angola.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Yellow Fever in Africa 2010 and 2011 per WHO</td></tr>
</tbody></table>
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<o:p><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><br /></span></o:p></div>
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<b style="mso-bidi-font-weight: normal;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span style="mso-spacerun: yes;"> </span>Current outbreaks <o:p></o:p></span></b></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Despite a vaccination rate of 70% in
2015, Angola and neighbouring countries are currently experiencing an outbreak
of YFV which originated in Angola in 2015 and is spreading into neighbouring
mainly by travel.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">In Angola, 2893 suspected cases with 788
confirmed cases and 325 deaths have been reported since Dec 2015. Cases in
Kenya (2), Sao Tome and Principe (2), Democratic Republic of Congo (44
imported/8 locally transmitted including 2 sylvatic), China (11) and possibly Ethiopia
<span style="mso-spacerun: yes;"> </span>(22) have been linked to outbreak in Angola
highlighting the contribution of travel to the spread of YFV by travel whereas
the outbreak in Uganda (7 confirmed and 68 suspected cases) is not linked to
Angola. <o:p></o:p></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgRxB6KYKsraCgPlxvCW9qqnazpFIdK2PrnTyz3XLhcx68THWnMI5gm2XIFK7wfOTpTdRxA5RLVn69R_wPRSreRqSEyox5tLYkPPWTxcNbp6upYYOd0ggnPLLFijExBZQcmokVXNlK8a3hZ/s1600/YFV+in+Angola.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgRxB6KYKsraCgPlxvCW9qqnazpFIdK2PrnTyz3XLhcx68THWnMI5gm2XIFK7wfOTpTdRxA5RLVn69R_wPRSreRqSEyox5tLYkPPWTxcNbp6upYYOd0ggnPLLFijExBZQcmokVXNlK8a3hZ/s640/YFV+in+Angola.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Number and distribution of cases linked to the current outbreak in Angola (excluding China)</td></tr>
</tbody></table>
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<o:p><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"> </span></o:p><span style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Of particular concern is the
introduction of YFV to China since Angola is home to a large Chinese community.
ZIKV was originally introduced to Asia from Africa before causing the current
epidemic in the Americas and CHIKV spread from Kenya to Asia before being
introduced to the Pacific, South America and the Caribbean.</span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Spread of YFV however might be limited
since individuals with DENV immunity in DENV endemic areas might not become
infected with YFV due to cross-protection which might explain the absence of YF
in Asia, although other factors such as the higher dependence of YFV on a
sylvatic transmission cycle and the higher mortality compared to DENV or ZIKV
might contribute to the absence of YFV outside of Africa and South America. <o:p></o:p></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Notwithstanding, the current outbreak in
Angola is a major concern for the region.<o:p></o:p></span></div>
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<w:LsdException Locked="false" Priority="11" QFormat="true" Name="Subtitle"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Salutation"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Date"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text First Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Heading"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Body Text Indent 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Block Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Hyperlink"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="FollowedHyperlink"/>
<w:LsdException Locked="false" Priority="22" QFormat="true" Name="Strong"/>
<w:LsdException Locked="false" Priority="20" QFormat="true" Name="Emphasis"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Document Map"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Plain Text"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="E-mail Signature"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Top of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Bottom of Form"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal (Web)"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Acronym"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Address"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Cite"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Code"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Definition"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Keyboard"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Preformatted"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Sample"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Typewriter"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="HTML Variable"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Normal Table"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="annotation subject"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="No List"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Outline List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Simple 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Classic 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Colorful 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Columns 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Grid 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table List 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table 3D effects 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Contemporary"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Elegant"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Professional"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Subtle 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Web 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Balloon Text"/>
<w:LsdException Locked="false" Priority="39" Name="Table Grid"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Table Theme"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 1"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 2"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 3"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 4"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 5"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 6"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 7"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 8"/>
<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
Name="Note Level 9"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Placeholder Text"/>
<w:LsdException Locked="false" Priority="1" QFormat="true" Name="No Spacing"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading"/>
<w:LsdException Locked="false" Priority="61" Name="Light List"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 1"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 1"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 1"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 1"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 1"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 1"/>
<w:LsdException Locked="false" SemiHidden="true" Name="Revision"/>
<w:LsdException Locked="false" Priority="34" QFormat="true"
Name="List Paragraph"/>
<w:LsdException Locked="false" Priority="29" QFormat="true" Name="Quote"/>
<w:LsdException Locked="false" Priority="30" QFormat="true"
Name="Intense Quote"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 1"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 1"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 1"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 1"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 1"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 1"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 1"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 1"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 2"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 2"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 2"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 2"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 2"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 2"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 2"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 2"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 2"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 2"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 2"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 2"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 2"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 2"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 3"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 3"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 3"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 3"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 3"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 3"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 3"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 3"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 3"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 3"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 3"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 3"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 3"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 3"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 4"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 4"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 4"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 4"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 4"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 4"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 4"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 4"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 4"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 4"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 4"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 4"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 4"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 4"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 5"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 5"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 5"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 5"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 5"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 5"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 5"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 5"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 5"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 5"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 5"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 5"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 5"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 5"/>
<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 6"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 6"/>
<w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 6"/>
<w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 6"/>
<w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 6"/>
<w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 6"/>
<w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 6"/>
<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 6"/>
<w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 6"/>
<w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 6"/>
<w:LsdException Locked="false" Priority="70" Name="Dark List Accent 6"/>
<w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 6"/>
<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 6"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 6"/>
<w:LsdException Locked="false" Priority="19" QFormat="true"
Name="Subtle Emphasis"/>
<w:LsdException Locked="false" Priority="21" QFormat="true"
Name="Intense Emphasis"/>
<w:LsdException Locked="false" Priority="31" QFormat="true"
Name="Subtle Reference"/>
<w:LsdException Locked="false" Priority="32" QFormat="true"
Name="Intense Reference"/>
<w:LsdException Locked="false" Priority="33" QFormat="true" Name="Book Title"/>
<w:LsdException Locked="false" Priority="37" SemiHidden="true"
UnhideWhenUsed="true" Name="Bibliography"/>
<w:LsdException Locked="false" Priority="39" SemiHidden="true"
UnhideWhenUsed="true" QFormat="true" Name="TOC Heading"/>
<w:LsdException Locked="false" Priority="41" Name="Plain Table 1"/>
<w:LsdException Locked="false" Priority="42" Name="Plain Table 2"/>
<w:LsdException Locked="false" Priority="43" Name="Plain Table 3"/>
<w:LsdException Locked="false" Priority="44" Name="Plain Table 4"/>
<w:LsdException Locked="false" Priority="45" Name="Plain Table 5"/>
<w:LsdException Locked="false" Priority="40" Name="Grid Table Light"/>
<w:LsdException Locked="false" Priority="46" Name="Grid Table 1 Light"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark"/>
<w:LsdException Locked="false" Priority="51" Name="Grid Table 6 Colorful"/>
<w:LsdException Locked="false" Priority="52" Name="Grid Table 7 Colorful"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 1"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 1"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 1"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 1"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 1"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 2"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 2"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 2"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 2"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 2"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 3"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 3"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 3"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 3"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 3"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 4"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 4"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 4"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 4"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 4"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 4"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 4"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 5"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 5"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 5"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 5"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 5"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 5"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 5"/>
<w:LsdException Locked="false" Priority="46"
Name="Grid Table 1 Light Accent 6"/>
<w:LsdException Locked="false" Priority="47" Name="Grid Table 2 Accent 6"/>
<w:LsdException Locked="false" Priority="48" Name="Grid Table 3 Accent 6"/>
<w:LsdException Locked="false" Priority="49" Name="Grid Table 4 Accent 6"/>
<w:LsdException Locked="false" Priority="50" Name="Grid Table 5 Dark Accent 6"/>
<w:LsdException Locked="false" Priority="51"
Name="Grid Table 6 Colorful Accent 6"/>
<w:LsdException Locked="false" Priority="52"
Name="Grid Table 7 Colorful Accent 6"/>
<w:LsdException Locked="false" Priority="46" Name="List Table 1 Light"/>
<w:LsdException Locked="false" Priority="47" Name="List Table 2"/>
<w:LsdException Locked="false" Priority="48" Name="List Table 3"/>
<w:LsdException Locked="false" Priority="49" Name="List Table 4"/>
<w:LsdException Locked="false" Priority="50" Name="List Table 5 Dark"/>
<w:LsdException Locked="false" Priority="51" Name="List Table 6 Colorful"/>
<w:LsdException Locked="false" Priority="52" Name="List Table 7 Colorful"/>
<w:LsdException Locked="false" Priority="46"
Name="List Table 1 Light Accent 1"/>
<w:LsdException Locked="false" Priority="47" Name="List Table 2 Accent 1"/>
<w:LsdException Locked="false" Priority="48" Name="List Table 3 Accent 1"/>
<w:LsdException Locked="false" Priority="49" Name="List Table 4 Accent 1"/>
<w:LsdException Locked="false" Priority="50" Name="List Table 5 Dark Accent 1"/>
<w:LsdException Locked="false" Priority="51"
Name="List Table 6 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="52"
Name="List Table 7 Colorful Accent 1"/>
<w:LsdException Locked="false" Priority="46"
Name="List Table 1 Light Accent 2"/>
<w:LsdException Locked="false" Priority="47" Name="List Table 2 Accent 2"/>
<w:LsdException Locked="false" Priority="48" Name="List Table 3 Accent 2"/>
<w:LsdException Locked="false" Priority="49" Name="List Table 4 Accent 2"/>
<w:LsdException Locked="false" Priority="50" Name="List Table 5 Dark Accent 2"/>
<w:LsdException Locked="false" Priority="51"
Name="List Table 6 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="52"
Name="List Table 7 Colorful Accent 2"/>
<w:LsdException Locked="false" Priority="46"
Name="List Table 1 Light Accent 3"/>
<w:LsdException Locked="false" Priority="47" Name="List Table 2 Accent 3"/>
<w:LsdException Locked="false" Priority="48" Name="List Table 3 Accent 3"/>
<w:LsdException Locked="false" Priority="49" Name="List Table 4 Accent 3"/>
<w:LsdException Locked="false" Priority="50" Name="List Table 5 Dark Accent 3"/>
<w:LsdException Locked="false" Priority="51"
Name="List Table 6 Colorful Accent 3"/>
<w:LsdException Locked="false" Priority="52"
Name="List Table 7 Colorful Accent 3"/>
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<div style="text-align: justify;">
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=International+journal+of+infectious+diseases+%3A+IJID+%3A+official+publication+of+the+International+Society+for+Infectious+Diseases&rft_id=info%3Apmid%2F27156836&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Yellow+fever+cases+in+Asia%3A+primed+for+an+epidemic.&rft.issn=1201-9712&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Wasserman+S&rft.au=Tambyah+PA&rft.au=Lim+PL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=International+journal+of+infectious+diseases+%3A+IJID+%3A+official+publication+of+the+International+Society+for+Infectious+Diseases&rft_id=info%3Apmid%2F27156836&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Yellow+fever+cases+in+Asia%3A+primed+for+an+epidemic.&rft.issn=1201-9712&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Wasserman+S&rft.au=Tambyah+PA&rft.au=Lim+PL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Further reading</span></u></span></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><div style="text-align: justify;">
Wasserman S, Tambyah PA, & Lim PL (2016). Yellow fever cases in Asia: primed for an epidemic. <span style="font-style: italic;">International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27156836" rev="review">27156836</a></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><div style="text-align: justify;">
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Lancet+Infectious+Diseases&rft_id=info%3Adoi%2F10.1016%2FS1473-3099%2801%2900016-0&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Yellow+fever%3A+an+update&rft.issn=14733099&rft.date=2001&rft.volume=1&rft.issue=1&rft.spage=11&rft.epage=20&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1473309901000160&rft.au=Monath%2C+T.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Monath, T. (2001). Yellow fever: an update <span style="font-style: italic;">The Lancet Infectious Diseases, 1</span> (1), 11-20 DOI: <a href="http://dx.doi.org/10.1016/S1473-3099(01)00016-0" rev="review">10.1016/S1473-3099(01)00016-0</a></span> </div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+New+England+journal+of+medicine&rft_id=info%3Apmid%2F27276108&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Yellow+Fever+in+Angola+and+Beyond+-+The+Problem+of+Vaccine+Supply+and+Demand.&rft.issn=0028-4793&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Barrett+AD&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Barrett AD (2016). Yellow Fever in Angola and Beyond - The Problem of Vaccine Supply and Demand. <span style="font-style: italic;">The New England journal of medicine</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27276108" rev="review">27276108</a></span> </span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Expert+review+of+vaccines&rft_id=info%3Apmid%2F27267203&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Questions+regarding+the+safety+and+duration+of+immunity+following+live+yellow+fever+vaccination.&rft.issn=1476-0584&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Amanna+IJ&rft.au=Slifka+MK&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Amanna IJ, & Slifka MK (2016). Questions regarding the safety and duration of immunity following live yellow fever vaccination. <span style="font-style: italic;">Expert review of vaccines</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27267203" rev="review">27267203</a></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Medical+journal%2C+Armed+Forces+India&rft_id=info%3Apmid%2F27257326&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dengue%2C+chikungunya+%E2%80%A6+and+the+missing+entity+-+Zika+fever%3A+A+new+emerging+threat.&rft.issn=0377-1237&rft.date=2016&rft.volume=72&rft.issue=2&rft.spage=157&rft.epage=63&rft.artnum=&rft.au=Tilak+R&rft.au=Ray+S&rft.au=Tilak+VW&rft.au=Mukherji+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Medical+journal%2C+Armed+Forces+India&rft_id=info%3Apmid%2F27257326&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dengue%2C+chikungunya+%E2%80%A6+and+the+missing+entity+-+Zika+fever%3A+A+new+emerging+threat.&rft.issn=0377-1237&rft.date=2016&rft.volume=72&rft.issue=2&rft.spage=157&rft.epage=63&rft.artnum=&rft.au=Tilak+R&rft.au=Ray+S&rft.au=Tilak+VW&rft.au=Mukherji+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Tilak R, Ray S, Tilak VW, & Mukherji S (2016). Dengue, chikungunya … and the missing entity - Zika fever: A new emerging threat. <span style="font-style: italic;">Medical journal, Armed Forces India, 72</span> (2), 157-63 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27257326" rev="review">27257326</a></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Infection%2C+genetics+and+evolution+%3A+journal+of+molecular+epidemiology+and+evolutionary+genetics+in+infectious+diseases&rft_id=info%3Apmid%2F22981999&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Evolutionary+and+ecological+factors+underlying+the+tempo+and+distribution+of+yellow+fever+virus+activity.&rft.issn=1567-1348&rft.date=2013&rft.volume=13&rft.issue=&rft.spage=198&rft.epage=210&rft.artnum=&rft.au=Carrington+CV&rft.au=Auguste+AJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology"><br /></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Infection%2C+genetics+and+evolution+%3A+journal+of+molecular+epidemiology+and+evolutionary+genetics+in+infectious+diseases&rft_id=info%3Apmid%2F22981999&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Evolutionary+and+ecological+factors+underlying+the+tempo+and+distribution+of+yellow+fever+virus+activity.&rft.issn=1567-1348&rft.date=2013&rft.volume=13&rft.issue=&rft.spage=198&rft.epage=210&rft.artnum=&rft.au=Carrington+CV&rft.au=Auguste+AJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology">Carrington CV, & Auguste AJ (2013). Evolutionary and ecological factors underlying the tempo and distribution of yellow fever virus activity. <span style="font-style: italic;">Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 13</span>, 198-210 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/22981999" rev="review">22981999</a></span> </span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Transactions+of+the+Royal+Society+of+Tropical+Medicine+and+Hygiene&rft_id=info%3Adoi%2F10.1093%2Ftrstmh%2Ftru081&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Yellow+fever%2C+Asia+and+the+East+African+slave+trade&rft.issn=0035-9203&rft.date=2014&rft.volume=108&rft.issue=8&rft.spage=519&rft.epage=519&rft.artnum=http%3A%2F%2Ftrstmh.oxfordjournals.org%2Fcgi%2Fdoi%2F10.1093%2Ftrstmh%2Ftru081&rft.au=Cathey%2C+J.&rft.au=Marr%2C+J.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Cathey, J., & Marr, J. (2014). Yellow fever, Asia and the East African slave trade <span style="font-style: italic;">Transactions of the Royal Society of Tropical Medicine and Hygiene, 108</span> (8), 519-519 DOI: <a href="http://dx.doi.org/10.1093/trstmh/tru081" rev="review">10.1093/trstmh/tru081</a></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+Pathogens&rft_id=info%3Adoi%2F10.1371%2Fjournal.ppat.0030075&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Out+of+Africa%3A+A+Molecular+Perspective+on+the+Introduction+of+Yellow+Fever+Virus+into+the+Americas&rft.issn=1553-7366&rft.date=2007&rft.volume=3&rft.issue=5&rft.spage=0&rft.epage=&rft.artnum=http%3A%2F%2Fdx.plos.org%2F10.1371%2Fjournal.ppat.0030075&rft.au=Bryant%2C+J.&rft.au=Holmes%2C+E.&rft.au=Barrett%2C+A.&rfe_dat=bpr3.included=1;bpr3.tags="><br /></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+Pathogens&rft_id=info%3Adoi%2F10.1371%2Fjournal.ppat.0030075&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Out+of+Africa%3A+A+Molecular+Perspective+on+the+Introduction+of+Yellow+Fever+Virus+into+the+Americas&rft.issn=1553-7366&rft.date=2007&rft.volume=3&rft.issue=5&rft.spage=0&rft.epage=&rft.artnum=http%3A%2F%2Fdx.plos.org%2F10.1371%2Fjournal.ppat.0030075&rft.au=Bryant%2C+J.&rft.au=Holmes%2C+E.&rft.au=Barrett%2C+A.&rfe_dat=bpr3.included=1;bpr3.tags=">Bryant, J., Holmes, E., & Barrett, A. (2007). Out of Africa: A Molecular Perspective on the Introduction of Yellow Fever Virus into the Americas <span style="font-style: italic;">PLoS Pathogens, 3</span> (5) DOI: <a href="http://dx.doi.org/10.1371/journal.ppat.0030075" rev="review">10.1371/journal.ppat.0030075</a></span> </span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=American+Entomologist&rft_id=info%3Adoi%2F10.1093%2Fae%2F37.1.14&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Evolutionary+Genetics+and+Arthropod-borne+Disease%3A+The+Yellow+Fever+Mosquito&rft.issn=1046-2821&rft.date=1991&rft.volume=37&rft.issue=1&rft.spage=14&rft.epage=26&rft.artnum=http%3A%2F%2Fae.oxfordjournals.org%2F%2Fcgi%2Fdoi%2F10.1093%2Fae%2F37.1.14&rft.au=Tabachnick%2C+W.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Tabachnick, W. (1991). Evolutionary Genetics and Arthropod-borne Disease: The Yellow Fever Mosquito <span style="font-style: italic;">American Entomologist, 37</span> (1), 14-26 DOI: <a href="http://dx.doi.org/10.1093/ae/37.1.14" rev="review">10.1093/ae/37.1.14</a></span> </span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"> <span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Lancet+%28London%2C+England%29&rft_id=info%3Apmid%2F10334247&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Facing+up+to+re-emergence+of+urban+yellow+fever.&rft.issn=0140-6736&rft.date=1999&rft.volume=353&rft.issue=9164&rft.spage=1541&rft.epage=&rft.artnum=&rft.au=Monath+TP&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Monath TP (1999). Facing up to re-emergence of urban yellow fever. <span style="font-style: italic;">Lancet (London, England), 353</span> (9164) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/10334247" rev="review">10334247</a></span> </span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+American+journal+of+tropical+medicine+and+hygiene&rft_id=info%3Apmid%2F1111351&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+relative+resistance+of+dengue-immune+monkeys+to+yellow+fever+virus.&rft.issn=0002-9637&rft.date=1975&rft.volume=24&rft.issue=1&rft.spage=115&rft.epage=7&rft.artnum=&rft.au=Theiler+M&rft.au=Anderson+CR&rfe_dat=bpr3.included=1;bpr3.tags="><br /></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+American+journal+of+tropical+medicine+and+hygiene&rft_id=info%3Apmid%2F1111351&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+relative+resistance+of+dengue-immune+monkeys+to+yellow+fever+virus.&rft.issn=0002-9637&rft.date=1975&rft.volume=24&rft.issue=1&rft.spage=115&rft.epage=7&rft.artnum=&rft.au=Theiler+M&rft.au=Anderson+CR&rfe_dat=bpr3.included=1;bpr3.tags=">Theiler M, & Anderson CR (1975). The relative resistance of dengue-immune monkeys to yellow fever virus. <span style="font-style: italic;">The American journal of tropical medicine and hygiene, 24</span> (1), 115-7 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/1111351" rev="review">1111351</a></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=BioMed+Research+International&rft_id=info%3Adoi%2F10.1155%2F2013%2F905043&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Is+There+a+Risk+of+Yellow+Fever+Virus+Transmission+in+South+Asian+Countries+with+Hyperendemic+Dengue%3F&rft.issn=2314-6133&rft.date=2013&rft.volume=2013&rft.issue=&rft.spage=1&rft.epage=9&rft.artnum=http%3A%2F%2Fwww.hindawi.com%2Fjournals%2Fbmri%2F2013%2F905043%2F&rft.au=Agampodi%2C+S.&rft.au=Wickramage%2C+K.&rfe_dat=bpr3.included=1;bpr3.tags="><br /></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=BioMed+Research+International&rft_id=info%3Adoi%2F10.1155%2F2013%2F905043&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Is+There+a+Risk+of+Yellow+Fever+Virus+Transmission+in+South+Asian+Countries+with+Hyperendemic+Dengue%3F&rft.issn=2314-6133&rft.date=2013&rft.volume=2013&rft.issue=&rft.spage=1&rft.epage=9&rft.artnum=http%3A%2F%2Fwww.hindawi.com%2Fjournals%2Fbmri%2F2013%2F905043%2F&rft.au=Agampodi%2C+S.&rft.au=Wickramage%2C+K.&rfe_dat=bpr3.included=1;bpr3.tags=">Agampodi, S., & Wickramage, K. (2013). Is There a Risk of Yellow Fever Virus Transmission in South Asian Countries with Hyperendemic Dengue? <span style="font-style: italic;">BioMed Research International, 2013</span>, 1-9 DOI: <a href="http://dx.doi.org/10.1155/2013/905043" rev="review">10.1155/2013/905043</a></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+American+journal+of+tropical+medicine+and+hygiene&rft_id=info%3Apmid%2F12887029&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Alteration+of+clinical+outcome+and+histopathology+of+yellow+fever+virus+infection+in+a+hamster+model+by+previous+infection+with+heterologous+flaviviruses.&rft.issn=0002-9637&rft.date=2003&rft.volume=68&rft.issue=6&rft.spage=695&rft.epage=703&rft.artnum=&rft.au=Xiao+SY&rft.au=Guzman+H&rft.au=da+Rosa+AP&rft.au=Zhu+HB&rft.au=Tesh+RB&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+American+journal+of+tropical+medicine+and+hygiene&rft_id=info%3Apmid%2F12887029&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Alteration+of+clinical+outcome+and+histopathology+of+yellow+fever+virus+infection+in+a+hamster+model+by+previous+infection+with+heterologous+flaviviruses.&rft.issn=0002-9637&rft.date=2003&rft.volume=68&rft.issue=6&rft.spage=695&rft.epage=703&rft.artnum=&rft.au=Xiao+SY&rft.au=Guzman+H&rft.au=da+Rosa+AP&rft.au=Zhu+HB&rft.au=Tesh+RB&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Xiao SY, Guzman H, da Rosa AP, Zhu HB, & Tesh RB (2003). Alteration of clinical outcome and histopathology of yellow fever virus infection in a hamster model by previous infection with heterologous flaviviruses. <span style="font-style: italic;">The American journal of tropical medicine and hygiene, 68</span> (6), 695-703 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12887029" rev="review">12887029</a></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">WHO situation report accessed 10 June 2016</span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">http://apps.who.int/iris/bitstream/10665/208818/1/yellowfeversitrep_2Jun2016_eng.pdf?ua=1</span></div>
thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-58397993755174043512016-06-07T07:24:00.000-04:002017-01-17T10:56:52.900-05:00Cytopathogenesis of ZIKV: IFTIM and viral entry/Hofbauer cells and the placenta<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Zika Virus (ZIKV) is an emerging member of the <i style="mso-bidi-font-style: normal;">Flaviviridae</i> that in the past months
spread to over 30 countries in the Americas alone that has been associated with
the emergence of microcephaly, a condition associated with abnormal brain
development, in Brazil and elsewhere. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Recent studies confirmed the presence of ZIKV in the
amniotic fluid as well in the brain and CNS of neonates, suggesting that ZIKV
can infect embryonal and foetal tissue by crossing the placental barrier. In
addition, ZIKV was detected in chronic villi of the placenta in one infected
mother, suggesting that ZIKV can indeed be transmitted vertically. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<b style="mso-bidi-font-weight: normal;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Cytopathic
effects of ZIKV in cell lines derived from human neural progenitor cells and
the role of HC in transmitting ZIKV <i style="mso-bidi-font-style: normal;">in
utero</i> <o:p></o:p></span></b></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Recently published studies which have been discussed
before, suggest that ZIKV can infect human neural progenitor cells (hNPC) derived from induced pluripotent stem cells,
brain organoids and neurospheres that are derived from embryonic stem cells or
induced pluripotent stem cell. Although these studies suggest that ZIKV can replicate
in these cells and induce apoptosis in these cells -results that by large
confirmed in mouse models - <span style="mso-spacerun: yes;"> </span>one of the
concerns is that those cells do not fully recapitulate foetal gene expression
when compared to human neural progenitor cells (hNP) which are directly
obtained from foetal brain tissue. In addition, iPSC are derived from
non-neural cells and therefore need to be validated prior using them to study
ZIKV pathogenesis in particular when investigating the potential consequences
of ZIKV on the development of the foetal brain. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Therefore, in a recent study two foetal cell lines
derived tissue at 16-19 days prof gestation were generated with cells being
infected with a recent ZIKV isolate from Puerto Rico isolated in 2015 (ZIKV
PRVABC59/ZIKV PR2015) at an MOI of 0.5. Following the infection with ZIKV
PR2015, the viral E protein can be detected at 48 hrs p.i. by
immunofluorescence in Nestrin positive with an infection rate of approximately
16% as measured by intracellular flow cytometry analysis, thus confirming
previous results obtained from infected hNPC and brain organoids that ZIKV can
indeed infect neuronal cells. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Concomitant with the detection of viral antigen, a
significant number of infected but not non-infected neighbouring cells exhibit pyknotic
cells and activated caspase-3 positive cells indicative of apoptosis,
confirming previous results obtained in brain organoids, hNPC, neurospheres and
in foetal mice brains thus suggesting that the induction of apoptosis in
neuronal by ZIKV is a common feature of ZIKV isolates belonging to the Asian
lineage. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In order to determine if the infection of neuronal
cells with ZIKV PRVABC559 induces the expression and secretion of cytokines
–and thus induces apoptosis of infected cells in a paracrine manner, bystander
apoptosis of neighbouring cells or releases neuroprotective factors that would
prevent apoptosis of neighbouring neuronal cells- the supernatant of ZIKV
infected cells was analysed for the presence of a total 102 human cytokines and
chemokines, including TNF-α, CCL2 and a neuroprotective cytokine, CX3CL1. In
contrast to neuronal cells treated with Poly (I:C) (a mimic of dsRNA that
induces the expression of cytokines), ZIKV PRVABC59 does not induce the
expression of cytokines at both 24 hrs and 72 hrs p.i.. As discussed before,
ZIKV infection of cell lines and brain organoids activates TLR-3 and inhibition
of TLR-3 has been reported to increase ZIKV replication, thus suggesting that
ZIKV inhibits antiviral signaling pathways downstream of TLR-3 albeit not
completely. In line with these results, the viral NS5 protein has recently been
reported to inhibit STAT2 mediated signaling by preventing the nuclear import
of STAT2 in a species specific manner. Although the role of NS5 has not been
studied in hNP, hNPC or brain organoids, it might be possible that ZIKV PR2015
NS5 inhibits STAT2 in these model systems in a similar way. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Similar to hNP cells, THP-1 cells also failed to
induce the expression of cytokines, including Interferon-α. These results are
also important when investigating the possibility of productive ZIKV
replication in placental cells. As discussed before, placental cells express
high levels of Interferon-λ1 (IFN-λ1), thus potentially inhibiting ZIKV
replication; assuming that ZIKV prevents the induction of IFN-λ1, ZIKV might
be able to replicate in placental cells albeit maybe to lower levels when
compared to hNP. <o:p></o:p></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">The notion that ZIKV can replicate in placental cells at
low levels is supported by recent findings that in syncytioblasts
(differentiated cytotrophoblasts; CTB) derived from healthy donors ZIKV PR2015 persistent
viral RNA can be detected up to 72 hrs p.i. concomitant with the release of
infectious viral particles up to 96 hrs p.i., the latter increasing five-fold
between 72 and 96 hrs p.i. The infection of CTB (as well as Hofbauer cells, see
below) with ZIKV PR2015 induces an increase in IFNB1 transcripts in the absence
of Interferon-β secretion indicating that ZIKV might inhibit secretion of IFN-β
and/or the translation of IFNB1 mRNA. In this context it is interesting to note
that both Coxsackievirus B and Poliovirus encode for viral proteins that
interfere with the cellular secretory pathway and that a chimeric yellow
fever/dengue virus is released in secretory vesicles suggesting that ZIKV might
inhibit the secretion of IFN by diverting the cellular secretory pathway in
favour of the release of viral particles. Further studies are however
warranted. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">The findings that ZIKV PR2015 can replicate in
placental cells seem at first to contradict previous results indicating that
ZIKV replication might be inhibited in placental cells due to the naturally
high levels of IFN- λ1. In contrast to the most recent findings however, the
previous results suggested that the supernatant of human placental cells might
prevent the replication of ZIKV FSS13025 and ZIKV MR766 in permissive JEG-3
cells, whereas the current study examined if placental cells per se are
permissive to ZIKV. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In contrast to hNP, the infection of Hofbauer cells
(HC), M2 type macrophages that are considered to be anti-inflammatory, with
ZIKV PR2015 not only supports viral replication with high viral titres
detectable as early as 48 hrs p.i., but also increased secretion of IFN-α,
IL-6, MCP-1 and IP-10, suggesting that ZIKV infection of HC –similar to other
viruses- induces a strong antiviral response. In doing so, ZIKV infection of HC
might protect uninfected bystander cells from being infected and indeed may
activate and induce the maturation of monocyte derived dendritic cells, thus
priming adaptive T cell response similar to DENV infected monocyte derived
cells. However, infection of HC has also been implicated in contributing to the
infection of embryonal cells by crossing the placental barrier and infection
embryonal/foetal neuronal precursor cells.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">The induction of the expression of genes encoding for
pro-inflammatory cytokines and antiviral chemokines by ZIKV is preceded by the
induction of the expression of retinoic acid inducible gene -1 (RIG1) like
receptor (RLR) as well as downstream antiviral genes including MDA5, DDX58,
DHX58, and IFIT-1/-2/-3. Interestingly, gene expression analysis of foetal
radial glial cells in mouse pups infected with ZIKV SZ01 revealed a similar
induction of the antiviral response, suggesting that at least in the foetal
brain of immunocompetent mice ZIKV can elicit a strong antiviral response. <o:p></o:p></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh8oVWNstz4vkbFMgScZoIvtwUf0Eh_TKx4nkMT0PYK95retqlLLpKIf4vq8f8qPgGCzJngM83QBNhHoG6Vvg-GEY4FkCTXkc1ezMVKQ6PoT7HkUkaxz7c184WRlIRd0WXU1KWqZIp2_bxk/s1600/ZIKV+cytopahthology.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh8oVWNstz4vkbFMgScZoIvtwUf0Eh_TKx4nkMT0PYK95retqlLLpKIf4vq8f8qPgGCzJngM83QBNhHoG6Vvg-GEY4FkCTXkc1ezMVKQ6PoT7HkUkaxz7c184WRlIRd0WXU1KWqZIp2_bxk/s640/ZIKV+cytopahthology.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Expression of MDA5, RIG-1, IFIT-1, IFIT-2 and IFIT-3 is increased<br />
in ZIKV SZ01 infected glial cells</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In conclusion, ZIKV PR2015 infected both placental
cells and Hofbauer cells, albeit with different kinetics. From the current data
it is not clear whether Hofbauer cells get infected first and then infect
placental cells, or vice versa (which seems to be unlikely). It is important to
note that HC are present in the placenta up to 18 weeks gestational age.
Transplacental transmission however is not unique to ZIKV. In the past, HBV has
been shown to cross the placental barrier, probably by cell-to-cell spread. <span style="mso-spacerun: yes;"> </span>In contrast to ZIKV however most infections
occur during the third trimester whereas ZIKV transmission predominantly occurs
within the first two trimesters. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In any case, the infection of either of both cell
types might be responsible for the transmission to the developing foetus, in
particular neural progenitor cells. Infected hNP in contrast to HC and
placental cells do not produce pro-inflammatory and antiviral chemokines but
undergo apoptosis; interestingly, infected HC do not undergo apoptosis whilst
producing both pro-inflammatory and antiviral chemokines. So far no gene expression
data are available to determine if ZIKV regulates the expression of genes
related to apoptosis, autophagy or the DNA damage repair. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<b style="mso-bidi-font-weight: normal;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span></b>
<b style="mso-bidi-font-weight: normal;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">ZIKV and IFTIM: inhibition of viral
replication and promoting apoptosis?</span></b></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">IFN-induced transmembrane (IFITM) proteins are
critical mediators of the host antiviral and antibacterial response with IFTIM-1,
-2 and -3 blocking the entry of a broad spectrum of RNA viruses including
Influenza A virus, SARS-CoV, West Nile Virus (WNV), Dengue Virus (DENV) and a reporter
virus carrying the envelope of Omsk hemorrhagic fever virus. In the case of DNA
viruses, neither IFTM-1 nor IFTM-2 or IFTM-3 preventing the entry of Human
Cytomegalovirus (HCMV), Human Papillomavirus (HPV) nor Adenovirus whilst
African Swine Fever (ASFV) isolate Ba71V induces the expression of IFTIM-2 in
Vero cells, thus preventing decapsidation of the viral particle and viral
entry. In the case of ZIKV, the infection of Vero cells but not human or murine
fibroblasts as well as Hela cells with ZIKV MR766 (and in the case of HeLa
cells, ZIKV FSS13025) induces extensive apoptosis of infected cells 72 hrs p.i.
. In ZIKV MR766 infected hNPC, IFTIM-2 is downregulated, suggesting that
IFTIM-2 downregulation might contribute to ZIKV induced apoptosis via
decreasing BAG-3 dependent paracrine prosurvival signaling. The importance of
IFTIM for the survival of ZIKV MR766 or ZIKV FSS13025 infected HeLa cells is
evident from recently published experiments showing that in HeLa cells expressing
shIFTIM3 (thus downregulating the expression of both IFTIM-2 and -3) viral
induced apoptosis is significantly increased at 72 hrs p.i. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjsLmwMGH_GlDxu2d3WXEPLyF-sm2ytin1AoGykANWoPGsd0Zx6MXTYSJysHDaugT_u0F5A8Wgwq8mW3UoofHerMmUJkiqHWOdUihq04VSQvUyXK48QWuBJjUiy6OT5zEy-Kk-eh3I5bzTk/s1600/ZIKV+cytopahthology.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjsLmwMGH_GlDxu2d3WXEPLyF-sm2ytin1AoGykANWoPGsd0Zx6MXTYSJysHDaugT_u0F5A8Wgwq8mW3UoofHerMmUJkiqHWOdUihq04VSQvUyXK48QWuBJjUiy6OT5zEy-Kk-eh3I5bzTk/s640/ZIKV+cytopahthology.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV entry might be dependent of IFTIM-2/-3 and inhibited by ZIKV at late time points<br />
p.i. </td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In addition to contributing to the induction of apoptosis
in infected cells, the deletion of IFTIM-3 in murine fibroblasts also increases
the replication of (mouse adapted) ZIKV MR766 and which can be reversed by
overexpression of IFTIM-3. Moreover, overexpression of IFTIM-3 in human A549
cells decreases the replication of both ZIKV MR766 and ZIKV FSS130025 probably
by inducing antiviral signaling pathways, preventing decapsidation similar to
WNV, DENV and ASFV and/or promoting the degradation of endosomes containing the
viral capsid via fusion with the lysosome. From an experimental point of view,
the recently described infectious clone of ZIKV might be modified to allow for
live cell imaging of ZIKV entry in the absence of IFTIM-2 and -3.</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">It should be emphasized that this mechanism does not
apply to the initial infection but only would prevent reinfection of already
infected cells. Therefore, further research using a replication-defective virus
or UV inactivated virus is needed to clarify the role of IFTIM in viral entry. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">As described for VSV-G and EBOV in a <a href="http://virologytidbits.blogspot.com/2014/07/autophagy-endosomes-and-viral-entry.html" target="_blank">previous posting</a>,
viral entry and subsequent targeting of viral capsid(s) to the lysosome might
involve components of autophagy machinery, in particular UVRAG, thus promoting
the formation of LBPA positive acidic vesicles. Although it has not been
demonstrated for ZIKV, ZIKV entry might be dependent on ATG9. In this scenario,
absence of ATG9 might promote the formation of LBPA positive acidic vesicles
similar to Bluetongue Virus.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiej4E6qa9AHM38Vgg9-5rYUwdTsAtezFzIPP1bbIew3MgKMBwYVpa2e2yivSpkz6eBSDkqxqv70swlsvIJlRca6OMJ6YizTperBl2pd_-kIPnF6-yEh67vcYuh4zwTcWZZQK5R6DJM1TI-/s1600/ZIKV+cytopahthology.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiej4E6qa9AHM38Vgg9-5rYUwdTsAtezFzIPP1bbIew3MgKMBwYVpa2e2yivSpkz6eBSDkqxqv70swlsvIJlRca6OMJ6YizTperBl2pd_-kIPnF6-yEh67vcYuh4zwTcWZZQK5R6DJM1TI-/s640/ZIKV+cytopahthology.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV capsid might localise to LBPA positive acidic vesicles in a UVRAG dependent manner</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Further studies are however needed to establish if a deficiency
or the expression of a mutant allele of the gene encoding for IFTIM-3
contributes to the spread of ZIKV in the Americas and increases susceptibility
of foetuses to ZIKV infection or contributes to the vertical transmission of
ZIKV. Data from Asia suggest the prevalence of a mutant rs12252-C allele
(encoding a mutant form of IFTM-3) thus rendering individuals for increased
risk of severe influenza. Whether this also contributed to the spread of ZIKV
in Asia is however not clear</span><span style="font-family: "helvetica";">.</span></div>
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<span style="font-family: "helvetica"; mso-ansi-language: EN-US;"><br /></span></div>
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padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Further reading</span></u></span><span style="float: left; padding: 5px;"><u><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><br /></span></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span><span style="float: left; padding: 5px;"><u><br /></u></span>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27162029&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Depletes+Neural+Progenitors+in+Human+Cerebral+Organoids+through+Activation+of+the+Innate+Immune+Receptor+TLR3.&rft.issn=1934-5909&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Dang+J&rft.au=Tiwari+SK&rft.au=Lichinchi+G&rft.au=Qin+Y&rft.au=Patil+VS&rft.au=Eroshkin+AM&rft.au=Rana+TM&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Dang J, Tiwari SK, Lichinchi G, Qin Y, Patil VS, Eroshkin AM, & Rana TM (2016). Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3. <span style="font-style: italic;">Cell stem cell</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27162029" rev="review">27162029</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+Reports&rft_id=info%3Adoi%2F10.1016%2Fj.celrep.2016.05.074&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+IFITMs+Inhibit+Zika+Virus+Replication&rft.issn=22111247&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124716306878&rft.au=Savidis%2C+G.&rft.au=Perreira%2C+J.&rft.au=Portmann%2C+J.&rft.au=Meraner%2C+P.&rft.au=Guo%2C+Z.&rft.au=Green%2C+S.&rft.au=Brass%2C+A.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Savidis, G., Perreira, J., Portmann, J., Meraner, P., Guo, Z., Green, S., & Brass, A. (2016). The IFITMs Inhibit Zika Virus Replication <span style="font-style: italic;">Cell Reports</span> DOI: <a href="http://dx.doi.org/10.1016/j.celrep.2016.05.074" rev="review">10.1016/j.celrep.2016.05.074</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Current+opinion+in+virology&rft_id=info%3Apmid%2F24480526&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=IFITM+proteins-cellular+inhibitors+of+viral+entry.&rft.issn=1879-6257&rft.date=2014&rft.volume=4&rft.issue=&rft.spage=71&rft.epage=7&rft.artnum=&rft.au=Smith+S&rft.au=Weston+S&rft.au=Kellam+P&rft.au=Marsh+M&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Smith S, Weston S, Kellam P, & Marsh M (2014). IFITM proteins-cellular inhibitors of viral entry. <span style="font-style: italic;">Current opinion in virology, 4</span>, 71-7 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24480526" rev="review">24480526</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PloS+one&rft_id=info%3Apmid%2F24827144&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+antiviral+restriction+factors+IFITM1%2C+2+and+3+do+not+inhibit+infection+of+human+papillomavirus%2C+cytomegalovirus+and+adenovirus.&rft.issn=&rft.date=2014&rft.volume=9&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Warren+CJ&rft.au=Griffin+LM&rft.au=Little+AS&rft.au=Huang+IC&rft.au=Farzan+M&rft.au=Pyeon+D&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Warren CJ, Griffin LM, Little AS, Huang IC, Farzan M, & Pyeon D (2014). The antiviral restriction factors IFITM1, 2 and 3 do not inhibit infection of human papillomavirus, cytomegalovirus and adenovirus. <span style="font-style: italic;">PloS one, 9</span> (5) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24827144" rev="review">24827144</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+pathogens&rft_id=info%3Apmid%2F25807108&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=HCV+induces+the+expression+of+Rubicon+and+UVRAG+to+temporally+regulate+the+maturation+of+autophagosomes+and+viral+replication.&rft.issn=1553-7366&rft.date=2015&rft.volume=11&rft.issue=3&rft.spage=&rft.epage=&rft.artnum=&rft.au=Wang+L&rft.au=Tian+Y&rft.au=Ou+JH&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Wang L, Tian Y, & Ou JH (2015). HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. <span style="font-style: italic;">PLoS pathogens, 11</span> (3) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25807108" rev="review">25807108</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+biological+chemistry&rft_id=info%3Apmid%2F27036941&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Entry+of+Bluetongue+Virus+Capsid+Requires+the+Late+Endosome-specific+Lipid+Lysobisphosphatidic+Acid.&rft.issn=0021-9258&rft.date=2016&rft.volume=291&rft.issue=23&rft.spage=12408&rft.epage=19&rft.artnum=&rft.au=Patel+A&rft.au=Mohl+BP&rft.au=Roy+P&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Patel A, Mohl BP, & Roy P (2016). Entry of Bluetongue Virus Capsid Requires the Late Endosome-specific Lipid Lysobisphosphatidic Acid. <span style="font-style: italic;">The Journal of biological chemistry, 291</span> (23), 12408-19 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27036941" rev="review">27036941</a></span> </span></div>
<br />thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-40252833668050807152016-06-06T21:19:00.000-04:002016-06-06T21:19:00.394-04:00<a href="http://www.mphonline.org/zika-virus/"><img alt="Zika Virus 101" border="0" src="http://www.mphonline.org/wp-content/uploads/2016/04/ZikaVirus.jpg" width="500" /></a><br />
Source: <a href="http://www.mphonline.org/">MPHOnline.org</a>thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-31816223924070231832016-05-30T16:21:00.003-04:002016-05-30T20:13:00.356-04:00ZIKV: ATM dependent signalling, VRK1, autophagy and the ER stress response in neuronal cells <div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Upon the induction of DNA damage, complex signaling
pathways are activated that regulate the ability of cells to detect and repair
the damage since both single and double strand DNA damage pose significant risk
to cell survival and transmission of unrepaired DNA damage to progeny is
associated not only with aging and cancer but also with neurodegenerative
diseases. During the DNA damage response (DDR) ds and ss DNA breaks are
recognised by ATM, ATR and DNA-PK kinases, which in turn activate signaling
pathways that converge on p53 and other scaffold proteins such as 53BP1, that
upon recruitment are localised at DNA repair foci. Nuclear Vaccinia related
kinase-1 (VRK1) is a nuclear Ser/Thr kinase that phosphorylates multiple
proteins involved in the DDR –including p53 and 53BP1- as well as promoting the
entry of cells into mitosis by phosphorylating Histone H3 at Thr-3 and Ser-10,
thus promoting nuclear condensation.</span><br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjLSFwJfZlcrbz5ElcDUYtZ8UMG-N7Cxc4BZQrbn3p1GUmONuegHBn6ueiNPJBUGfb_4sO05Xgy-QIRR3I15_xEglWy-Mm8MfhYVfbcaV5WGtqeQ6SMSFXFhyVqb1a5JEYb8GUQ1PHI2JU1/s1600/ZIKV+COPII+Endosome.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjLSFwJfZlcrbz5ElcDUYtZ8UMG-N7Cxc4BZQrbn3p1GUmONuegHBn6ueiNPJBUGfb_4sO05Xgy-QIRR3I15_xEglWy-Mm8MfhYVfbcaV5WGtqeQ6SMSFXFhyVqb1a5JEYb8GUQ1PHI2JU1/s640/ZIKV+COPII+Endosome.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Functions of VRK1 in mitotic entry</td></tr>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiyRdyEwCRMpQmfeV6k9q-TvWJpv62618l-Zv2AlpN_k_4ijfS4oFJ2tzWB0iVeML9jKjyYWxKYAUueYrLLEt_4KLaCKYLE6_t1FYhI4CEtJfmNwYCBbxPBToENlgiVBsarvAJ0JhPrdQAV/s1600/ZIKV+COPII+Endosome.005.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiyRdyEwCRMpQmfeV6k9q-TvWJpv62618l-Zv2AlpN_k_4ijfS4oFJ2tzWB0iVeML9jKjyYWxKYAUueYrLLEt_4KLaCKYLE6_t1FYhI4CEtJfmNwYCBbxPBToENlgiVBsarvAJ0JhPrdQAV/s640/ZIKV+COPII+Endosome.005.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Functions of VRK1 in ATM mediated signalling during DDR</td></tr>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In the case of p53, VRK1 stabilises
p53 by phosphorylating p53 at Thr-18 thus increasing p53 dependent gene
expression and preventing the degradation of p53 by MDM2. During the DDR, VRK1
is predominantly associated with chromatin remodeling and recruitment of 53BP1
to sites of DNA damage and promoting phosphorylation of H2AX at Ser139 in a ATM
and p53 dependent pathway as well as promoting the acetylation of both Histone
H3 and H4 by recruitment of p300/CBP.</span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica"; mso-ansi-language: EN-US;">In human cells, loss of VRK1 is associated with arrest
in G0 but not G2 phase of the cell cycle and mutations of </span><span style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;">VRK1 have been associated with complex motor and
sensory axonal neuropathy and microcephaly. Since in both ZIKV infected mice
brain cells and ZIKV infected human neuronal progenitor cells (hNPC) VKR1
expression is decreased, this supports the notion that the observed defects in
the neuronal defects are due to mitotic defects induced by ZIKV.<o:p></o:p></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiW4Eyq466wrPezfj0Z-iaS5pUa90ikxq2nXcFWegKmG3iX7C5MKywipRECt3F2smhdjmQ7kkJuDhmDllJDInVsMdjEymv6QmuYmUgjiY7X_Jn_w7hkBpIhmkvpYdQ5Ftctc1CAcTjWEeq2/s1600/ZIKV+COPII+Endosome.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiW4Eyq466wrPezfj0Z-iaS5pUa90ikxq2nXcFWegKmG3iX7C5MKywipRECt3F2smhdjmQ7kkJuDhmDllJDInVsMdjEymv6QmuYmUgjiY7X_Jn_w7hkBpIhmkvpYdQ5Ftctc1CAcTjWEeq2/s640/ZIKV+COPII+Endosome.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure and table: Gene changes in ZIKV infected foetal cells regarding components of<br />
the non canonical ULK signalling and VRK</td></tr>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimt5wj7Y7kKH8oPLO3Q_P_m0V1wVeSwQeL0fKWm3eJ4jtZ_tpzMDnxgI1z_Rr-DKfxrj10JfMEIiJiqoiZbliAw1qKTCYl8etGqOvnXvzpbOm3UjzSnQ1wW5I-FEMq3mPLyhHlhNmVqo38/s1600/ZIKV+COPII+Endosome.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimt5wj7Y7kKH8oPLO3Q_P_m0V1wVeSwQeL0fKWm3eJ4jtZ_tpzMDnxgI1z_Rr-DKfxrj10JfMEIiJiqoiZbliAw1qKTCYl8etGqOvnXvzpbOm3UjzSnQ1wW5I-FEMq3mPLyhHlhNmVqo38/s640/ZIKV+COPII+Endosome.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV and VRK1:inhibition of Histone H# phosphorylation </td></tr>
</tbody></table>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In
addition to promote the DDR and mitotic entry, the activation of VRK1 by
Polo-like kinase 3 (Plk3) is also required for MEK1 dependent fragmentation of
the Golgi during mitosis and the entry of cells into S phase by inducing the
expression of Cyclin D in CREB dependent manner; ZIKV mediated downregulation
of VRK1 therefore might not only prevent mitotic entry and the DDR but also
interferes with the fragmentation of the Golgi as well as entry of infected
cells into S phase. As described before, inhibition of mitotic entry by ZIKV
has been proposed to be associated with a prolonged S phase as evidenced by an
increase of BrdU positive cells in ZIKV infected foetal brain cells. If this is
the case, then ZIKV infection of G1 cells might either not downregulate cyclin
D1 expression per se but the observed decrease of Cyclin D expression might be
associated with an increase of S phase cells instead. Decreased levels of VKR1
therefore might therefore primarily associated with preventing mitotic entry.
Further studies are therefore needed to determine the pathways associated with
prolonging S phase v. preventing mitotic entry of ZIKV infected cells.</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhnSKDWFvAkY4w5XHdClUa9j0lRlQGKx4xtmt5-TRqFgSOc3r7T9ebYl1J-l74Ei7clR-FsXhY0rv6-ifZFV7SijZaZjAGvuJ6EbDknDGm5j67fCjG16HSoO7VTYIB_aU6o8ThYvxWxBskp/s1600/ZIKV+COPII+Endosome.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhnSKDWFvAkY4w5XHdClUa9j0lRlQGKx4xtmt5-TRqFgSOc3r7T9ebYl1J-l74Ei7clR-FsXhY0rv6-ifZFV7SijZaZjAGvuJ6EbDknDGm5j67fCjG16HSoO7VTYIB_aU6o8ThYvxWxBskp/s640/ZIKV+COPII+Endosome.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV, VRK1 and Cyclin D1</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;">Additionally,
VRK1 also induces the degradation of p53 in a DRAM1 dependent pathway via
autophagy; therefore, ZIKV might promote the degradation of p53 via Mdm2
dependent ubiquitination and subsequent proteasomal degradation of p53. <o:p></o:p></span></div>
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<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhCwdwZhvpnD7kuDtX4fXyQIlnV_SJ_cJLKxv4c8km28Xp-6IMZzK0oWXZ43Z5GQj7J59RjlgCkgVGdiFXvcRL5kzQ6_ZlAPHcJ_D7S1hfGAQG8WPwOTsTbkrADWcosNJ1LXllWatBMGYpY/s1600/ZIKV+COPII+Endosome.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhCwdwZhvpnD7kuDtX4fXyQIlnV_SJ_cJLKxv4c8km28Xp-6IMZzK0oWXZ43Z5GQj7J59RjlgCkgVGdiFXvcRL5kzQ6_ZlAPHcJ_D7S1hfGAQG8WPwOTsTbkrADWcosNJ1LXllWatBMGYpY/s640/ZIKV+COPII+Endosome.006.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV, ATM, VRK1, and p53: ZIKV may increase degradation of p53 via the proteasome<br />
and inhibit DRAM1 dependent autophagy</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Phosphorylation
of ATM at Ser-181 and ATM dependent formation of autophagosomes however can not
only be induced by DDR signaling but also ER stress signaling pathways, namely
by CHOP. Indeed, the infection of MDCK and HeLa GFP-LC3 cells with Dengue Virus
2 (DENV2) induces the formation of autophagosomes in the absence of apoptosis
in a ATM dependent manner since the inhibition of ATM using Caffeine or siATM
both increased the sensitivity of DENV2 infected MDCK cells to Camptothecin as
well as decreasing levels of LC3-II (autophagic flux was not determined) at 24
hrs p.i. . During later stages of infection, ATM is is induced in a ROS
dependent manner which either are accumulating due to increased PERK activity
or mitochondrial damage.</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;">In
the case of ZIKV, ATM therefore could be induced as a result of stalled
replication as proposed before, the induction of the ER stress response or
(especially at late stages of the replication cycle) due to the production of
mitochondrial ROS as a result of mitochondrial damage. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;">Despite
the increase in the formation of autophagosomes, autophagic flux in both DENV 2
and ZIKV infected cells however might be inhibited; in the case of DENV,
p62/SQSTM1 is degraded by the proteasome and in ZIKV infected hNPC the
expression of LAMP2 is downregulated. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;">In
addition, in ZIKV infected cells the clearance of misfolded proteins that
accumulate in the ER might be prevented by inhibition of ER-to Golgi COPII
dependent traffic and thus contribute to neuronal death similar to ULK1/2
double knockout mice. In ULK1/2 double knockout mice, a complex consisting of
SEC16A, SEC23 and SEC24A is activated by site specific of SEC16A by the cellular
ULK1/2, thus localising the complex to ER exit sites and promoting the
clearance of cargo via COPII dependent traffic. In order to investigate if ZIKV
disrupts this specific pathway however, neuronal cells need to be used since in
other cell lines this noncanonical role of ULK1/2 might not play an essential
role in the clearance of accumulated protein. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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conclusion, ZIKV might activate ATM upon DNA damage and/or the induction of the
ER stress response. In both cases, this response however might be abrogated due
to the downregulation of VKR1 and components of the COPII dependent ER to Golgi
trafficking pathway, leading to neuronal death. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;"><br /></span>
<span style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;"><br /></span>
<span style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;"><br /></span>
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<span style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;"><u>Further reading</u></span></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Arial; mso-bidi-font-weight: bold;"><br /></span>
</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Lamarche, B., Orazio, N., & Weitzman, M. (2010). The MRN complex in double-strand break repair and telomere maintenance </span><span style="font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-style: italic;">FEBS Letters, 584</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> (17), 3682-3695 DOI: </span><a href="http://dx.doi.org/10.1016/j.febslet.2010.07.029" rev="review" style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;">10.1016/j.febslet.2010.07.029</a></span></div>
<div style="text-align: justify;">
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+cell+science&rft_id=info%3Apmid%2F18713830&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=VRK1+phosphorylates+CREB+and+mediates+CCND1+expression.&rft.issn=0021-9533&rft.date=2008&rft.volume=121&rft.issue=Pt+18&rft.spage=3035&rft.epage=41&rft.artnum=&rft.au=Kang+TH&rft.au=Park+DY&rft.au=Kim+W&rft.au=Kim+KT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+cell+science&rft_id=info%3Apmid%2F18713830&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=VRK1+phosphorylates+CREB+and+mediates+CCND1+expression.&rft.issn=0021-9533&rft.date=2008&rft.volume=121&rft.issue=Pt+18&rft.spage=3035&rft.epage=41&rft.artnum=&rft.au=Kang+TH&rft.au=Park+DY&rft.au=Kim+W&rft.au=Kim+KT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Kang TH, Park DY, Kim W, & Kim KT (2008). VRK1 phosphorylates CREB and mediates CCND1 expression. <span style="font-style: italic;">Journal of cell science, 121</span> (Pt 18), 3035-41 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/18713830" rev="review">18713830</a></span> </span></div>
<div style="text-align: justify;">
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Molecular+and+Cellular+Biology&rft_id=info%3Adoi%2F10.1128%2FMCB.01341-08&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Plk3+Interacts+with+and+Specifically+Phosphorylates+VRK1+in+Ser342%2C+a+Downstream+Target+in+a+Pathway+That+Induces+Golgi+Fragmentation&rft.issn=0270-7306&rft.date=2008&rft.volume=29&rft.issue=5&rft.spage=1189&rft.epage=1201&rft.artnum=http%3A%2F%2Fmcb.asm.org%2Fcgi%2Fdoi%2F10.1128%2FMCB.01341-08&rft.au=Lopez-Sanchez%2C+I.&rft.au=Sanz-Garcia%2C+M.&rft.au=Lazo%2C+P.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> <span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Epigenetics&rft_id=info%3Apmid%2F25923214&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=VRK1+chromatin+kinase+phosphorylates+H2AX+and+is+required+for+foci+formation+induced+by+DNA+damage.&rft.issn=1559-2294&rft.date=2015&rft.volume=10&rft.issue=5&rft.spage=373&rft.epage=83&rft.artnum=&rft.au=Salzano+M&rft.au=Sanz-Garc%C3%ADa+M&rft.au=Monsalve+DM&rft.au=Moura+DS&rft.au=Lazo+PA&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Salzano M, Sanz-García M, Monsalve DM, Moura DS, & Lazo PA (2015). VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage. <span style="font-style: italic;">Epigenetics, 10</span> (5), 373-83 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25923214" rev="review">25923214</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+death+%26+disease&rft_id=info%3Apmid%2F26938301&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dengue-induced+autophagy%2C+virus+replication+and+protection+from+cell+death+require+ER+stress+%28PERK%29+pathway+activation.&rft.issn=&rft.date=2016&rft.volume=7&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Datan+E&rft.au=Roy+SG&rft.au=Germain+G&rft.au=Zali+N&rft.au=McLean+JE&rft.au=Golshan+G&rft.au=Harbajan+S&rft.au=Lockshin+RA&rft.au=Zakeri+Z&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Datan E, Roy SG, Germain G, Zali N, McLean JE, Golshan G, Harbajan S, Lockshin RA, & Zakeri Z (2016). Dengue-induced autophagy, virus replication and protection from cell death require ER stress (PERK) pathway activation. <span style="font-style: italic;">Cell death & disease, 7</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26938301" rev="review">26938301</a></span> </span></div>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-87176800935145850062016-05-24T11:27:00.001-04:002016-10-03T21:07:22.237-04:00ZIKV infection in mice: cell cycle defects as a cause for microcephaly? <div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Zika Virus (ZIKV) was first isolated in 1947 from a
sentinel monkey in Uganda and despite sporadic local outbreaks only caused mild
disease in humans. The emergence of ZIKV combined with severe pathogenicity in
South America as early as 2014 however raised questions about the molecular
evolution of ZIKV since ZIKV was previously only associated with arthralgia and
a mild febrile illness but not neuropathological disorders including abnormal
foetal brain development and Guillan-Barre Syndrome (GBS). <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">ZIKV is a flavivirus closely related to Dengue Virus
(DENV) with single stranded positive stranded RNA genome of approximately 10800
bp. Similar to DENV, the ZIKV RNA encodes for a single polyprotein that it is
cleaved into the structural (Capsid (C), pre-membrane (prM), and envelope (E))
and non-structural (NS1, NS2A, NS2B, NS3, NS4A, 2K, NS4B, and NS5) proteins
with the replication taking place in the cytoplasm of infected although at
least the C and NS5 proteins localise to the nucleolus and to nuclear speckles
respectively, suggesting that the nuclear localisation of these proteins might
be required for efficient viral replication. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Based on genetic and phylogenetic analyses, two
lineages can be identified, with epidemics in Micronesia/Yap in 2007, French
Polynesia 2013-2014 and the current epidemic in South America being linked to
the Asian lineage. Phylogenetic analyses of all contemporary strains share
greater homology to ZIKV P6-740 strain isolated from mosquitoes in Malaysia in
1966 rather than the ZIKV IbH-30656 isolated from Nigeria in 1968, suggesting
that the current strains circulating in the Pacific and South America are
rooted in the African lineage but are descendants of the ZIKV Malaysia/1966.
Further analysis revealed that the current Brazilian strains are closer related
to ZIKV H/PF/2013 (ZIKV French Polynesia/2013) rather than ZIKV FSM (Federal
States of Micronesia)/2007. Since the ZIKV outbreak in Polynesia but not in
Micronesia has been associated with an increased risk of GBS and of
microcephaly, it might be possible that ZIKV H/PF/2013 and the descendants
isolated in the Americas exhibit mutations that cause foetal brain
abnormalities and increase the risk of developing GBS. In order to investigate
if ZIKV H/PF/2013 is indeed more pathogenic than ZIKV FSM/2007 recently
developed mouse models might provide be useful. In addition, the use of the
recently developed infectious clone of ZIKV FSS1305 –a strain isolated in
Cambodia in 2010- might aid these studies by introducing mutations into viral
genes that can be found in isolates from the Americas and/or from French
Polynesia. The use of historical strains including the original ZIKV MR-766
isolate to study ZIKV related pathogenesis however is problematic since these
strains were originally propagated in mice brains and are therefore highly
adapted whereas modern isolates are propagated in mosquitoe C6/36 and Vero
cells, although historically the repeated passage of ZIKV MR-766 in mice brain
yielded important insights in ZIKV pathogenesis. Using mice however as a model
system for studying the teratogenicity of ZIKV is limited since offspring of
immunocompetent mice does not develop microcephaly, suggesting that in humans
other factors besides ZIKV infection are required for the development of
microcephaly. One of the contributing factors might be a previous infection or
vaccination against DENV, others might be co-infection with other pathogens
that allow ZIKV or ZIKV infected immune cells to cross the placental barrier
and infect the embryo.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">In the past months, the infection of brain organoids
and human neural precursor cells (hNPC) with ZIKV not only let to the
identification of the receptor that allows ZIKV entry into neural cells (Axl)
but also suggest how ZIKV induces abnormal brain development.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">As discussed in detail in previous posts, the
infection of hNPC and brain organoids downregulates the expression of genes
regulating multiple cellular pathways such as DNA repair, DNA replication and
cell cycle progression, suggesting that apoptosis is induced by stalled
replication forks and mitotic defects. In general, a model was proposed in
which ZIKV induces the depolarisation of mitochondria and inducing caspase-3
dependent apoptosis. <span style="mso-spacerun: yes;"> </span>Upregulation of
autophagy related genes (ATG) on the other might benefit viral replication by
increasing both lipophagy and the formation of viral replication centres whilst
at the same time contributing to autophagy mediated cell death. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Close analysis of mouse brains derived from
immunodeficient SJL mice pups but not wt C57BL/6 born to females infected with a
ZIKV strain isolated from Brazil (ZIKV BR) shows that cortical neurons as well
as neurons derived from the thalamus and hypothalamus exhibit nuclear debris
suggesting that ZIKV BR does induce apoptosis as well as exhibiting ocular
defects similar to human neonate patients and anatomical changes similar to
those seen in microcephaly in neonates.<span style="mso-spacerun: yes;">
</span>In a similar way, injection of mouse embryos with ZIKV SZ01 (Asian
lineage isolated from a Chinese patient) at E13.5 leads to cell cycle arrest as
measured by BrdU incorporation, apoptosis of neuronal cells and abnormal
differentiation of neural precursor cells suggesting that neuronal death is a
common feature of ZIKV infected pups. Furthermore, both ZIKV BR and ZIKV SZ01
replicates efficiently in brain tissue of immunodeficient mice despite not
being adapted to mouse cells. In a separate study, injection of ZIKV SZ01 into
pregnant C57BL/6 <i style="mso-bidi-font-style: normal;">in utero</i> (thus
bypassing the placental barrier) affects the cortical development of offspring
mice as early as 96 hrs p.i. concomitant with a downregulation of the
expression of genes related to cell proliferation and the negative regulation
of apoptosis whereas the expression of genes encoding for proteins involved in
antiviral signaling is increased, suggesting that ZIKV induces both apoptotic
and antiviral signaling pathways in embryonic cells. <o:p></o:p></span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHsRfvClgh1ULY5ncIxVZ2EG-1Oc0chnJTZJn6Hz7OkRLjDkhFkec_J04mD9bVKlbWx7NFer3uBG0YtwyEbe7m03S-1obVBnMOP_e7Pe2qp62nn2Fi0GTfS_HcncxGSHc-jDwtixBmCjrK/s1600/ZIKV+STAT2+mitotic+defect+and+recent+models.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHsRfvClgh1ULY5ncIxVZ2EG-1Oc0chnJTZJn6Hz7OkRLjDkhFkec_J04mD9bVKlbWx7NFer3uBG0YtwyEbe7m03S-1obVBnMOP_e7Pe2qp62nn2Fi0GTfS_HcncxGSHc-jDwtixBmCjrK/s640/ZIKV+STAT2+mitotic+defect+and+recent+models.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table: ZIKV induced increase of gene expression in E13.5 and E17.5 mice embryos </td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">The </span><i style="font-family: 'helvetica neue', arial, helvetica, sans-serif;">in utero</i><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">
infection of (mouse) foetal brains with ZIKV SZ01 also decreases the expression
of proteins that previously have been linked to the development of
microcephaly in particular those that are involved in the separation of
chromosomes during metaphase and anaphase, suggesting that ZIKV infected
embryonic and/or foetal cells might exhibit incomplete cytokinesis which may
lead to the formation of micronuclei and subsequent apoptosis. In a similar
way, hNPC infected with ZIKV MR766 exhibit a decrease in the expression of the
very same genes confirming that the downregulation of genes regulating mitotic
progression might contribute to the development of microcephaly in human
foetuses and neonates. Interestingly, the infection of hNPC with ZIKV MR766
also induces the downregulation of Aurora Kinase B, suggesting that the
induction of the NoCut checkpoint that regulates the abscission in response to chromosome
segregation defects both in yeast and animal cells might be inhibited thus
leading to mitotic defects.</span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhlIXaSTPDcCbLmNAJTRI76HNTJIvrMsIa_mXdLaChrHcqj7IjRzcnPfAUmYmodyI_6EK6NLh_ZAMGdViMRj8TAvzlxiS6rPOmtfbYdK7ctWGWDpIT2mQL_8Hopy64QKDTHC1XcgzDyqoXi/s1600/ZIKV+STAT2+mitotic+defect+and+recent+models.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhlIXaSTPDcCbLmNAJTRI76HNTJIvrMsIa_mXdLaChrHcqj7IjRzcnPfAUmYmodyI_6EK6NLh_ZAMGdViMRj8TAvzlxiS6rPOmtfbYdK7ctWGWDpIT2mQL_8Hopy64QKDTHC1XcgzDyqoXi/s640/ZIKV+STAT2+mitotic+defect+and+recent+models.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table: Downregulation of gene expression; genes related to microcephaly also regulate mitosis</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Since the NoCut checkpoint is induced by stalled DNA
replication forks, ZIKV infection might stabilise chromatin bridges. Under
normal circumstances chromatin bridges are protected by RAD50 and resolved by
APC</span><sup><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Cdh1</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: medium;"> </span></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> resulting in a delay of abscission but if this is the case in ZIKV infected cells remains to be seen. </span></sup></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Another possibility is however that the infection of
ZIKV prolongs S phase by the activation of intra S phase checkpoints and
subsequently arresting infected cells in G2 rather than M phase. This notion is
supported by flow cytometry analysis of ZIKV MR766 infected hNPC as well as by
measuring the presence of Histone H3-P (Ser10), a marker that allows the
differentiation between G2 and M phase by flow cytometry in ZIKV SZ01 infected
mouse embryonic cells. In addition to the observed G2 arrest, the latter also
exhibited duplicated centrosomes suggesting that ZIKV infected indeed do not
enter mitosis. As evidenced by the expression of Pax6, Sox2 and Tbr2, ZIKV mainly infects primary neuronal progenitor cells that undergo cell proliferation rather than differentiated neurons, although post mitotic neutrons may be infected as well unless ZIKV positive post mitotic neurons represent neurons that got initially infected prior differentiation and failed to undergo apoptosis prior differentiation. Alternatively, post mitotic neurons may be a infected as a result of viral spread following the infection of immature neurons. <o:p></o:p></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; mso-ansi-language: EN-US;">In contrast to other previously published papers using
isolates from Brazil of French Polynesia however, ZIKV SZ01 might cross the
placental barrier since intraperitoneal injection of ZIKV SZ01 causes abnormal
foetal brain development in C57BL/6 mice. Additionally, the results suggest
that in C57BL/6 the injection of ZIKV i.p. might not cause viraemia as
confirmed by previous studies but unfortunately, no side by side experiments
with other ZIKV isolates were performed.</span><span lang="EN-GB" style="font-family: "helvetica";"><o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Since the infection of susceptible cells with ZIKV
probably induces a TLR-3 dependent antiviral response and thus might induce
bystander apoptosis, further research is needed to elucidate the precise
signaling pathways that induce the activation of caspase-3. Here the use of
specific inhibitors is warranted. In addition, the contribution of autophagy to
cell death has not been established despite the reported upregulation of genes
such as Bmf, Irgm1, Bcl-2, Htt, Abl1 and Casp6 that are involved in the
regulation of the formation of autophagosomes. Since the overexpression of some
of the proteins –especially Bcl-2 and Bmf- inhibits rather than promotes the
formation of autophagosomes whereas the overexpression of Irgm-1 promotes
neuronal autophagy and survival of mouse neurons, the connection between ZIKV
induced autophagy and apoptosis might be more complex. Adding to the
complexity, the upregulation of Casp6 however might prevent p62/SQSTM-1
dependent selective autophagy despite the upregulation of Htt by cleaving Htt. In addition, cleavage of Beclin-1 by caspase-3 -which generates a C-terminal fragment of Beclin-1- might also inhibit the formation of autophagosomes. <o:p></o:p></span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-xTrtW428nqDAGPY7kqYD9jy4udnef00uKU569L49nUG1UHDaxCl00boUe70H0UzLcFNaE4kuFUYBkF2qnKCnAPn5W03PBHfdtCYCWtrt9agOcIhI9BA1Kj3e4uWjVXUmIxejz1YfuWOe/s1600/ZIKV+STAT2+mitotic+defect+and+recent+models.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-xTrtW428nqDAGPY7kqYD9jy4udnef00uKU569L49nUG1UHDaxCl00boUe70H0UzLcFNaE4kuFUYBkF2qnKCnAPn5W03PBHfdtCYCWtrt9agOcIhI9BA1Kj3e4uWjVXUmIxejz1YfuWOe/s640/ZIKV+STAT2+mitotic+defect+and+recent+models.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: HTT recognises p62/SQSTM1 and is involved in the recruitment of the ULK complex</td></tr>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-ansi-language: EN-US;">Interestingly, A549 cells infected with ZIKV H/PF/2013
do not exhibit autophagosomes or autophagosome-like vesicles whereas human skin
fibroblasts infected with ZIKV MR766 do. Both neurons and NPC infected with
ZIKV BR at an MOI of 10 exhibit large viral protein aggregates at 24 hrs p.i.
suggesting the presence viral replication centres whose precise nature is not
known. <o:p></o:p></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjOrO2xeK-ttZzWozzJ4visQDq3NRYBHDyHLgFLwSAljrHJsrq9lKh4lNI0QRPirRa_nEU_MpNmBFhnCx-71d-m9WTHPatfdifPZhN5nHeECzC2t0oXn4pdWlCAJFXzK2eocooOXlHWCay7/s1600/ZIKV+STAT2+mitotic+defect+and+recent+models.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjOrO2xeK-ttZzWozzJ4visQDq3NRYBHDyHLgFLwSAljrHJsrq9lKh4lNI0QRPirRa_nEU_MpNmBFhnCx-71d-m9WTHPatfdifPZhN5nHeECzC2t0oXn4pdWlCAJFXzK2eocooOXlHWCay7/s640/ZIKV+STAT2+mitotic+defect+and+recent+models.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Hypothetical network in which ZIKV induces the NoCut pathway<br />
and regulates autophagy </td></tr>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<b style="mso-bidi-font-weight: normal;"><span lang="EN-GB" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="mso-spacerun: yes;"> </span>ZIKV NS5
and STAT2: mitotic defect?<o:p></o:p></span></b></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span lang="EN-GB" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The NS5 protein derived from various members of
the <i style="mso-bidi-font-style: normal;">Flaviviridae</i> including DENV, WNV,
Spondweni Virus, YFV, JEV, Langat Virus (LGV), Yokose Virus (YOKV) and Usutu
Virus (USUV) has been shown to bind and degrade STAT2 and thus abrogate the
type I Interferon response in Vero cells. In a similar way, the expression of
ZIKV NS5 prevents the nuclear translocation of STAT2 by promoting the
degradation of STAT2 via ubiquitinylation and subsequent targeting to
proteasomes both in transfected and ZIKV Fortaleza infected cells in a species
dependent manner, e.g.in Vero, primary human fibroblasts and HEK 293T cells but
not in primary mouse fibroblasts derived from IFNAR -/- mice that are otherwise
permissible for ZIKV. Three features make NS5 an interesting protein. First, a
subfraction of NS5 localises to nuclear speckles in both infected and NS5
transfected cells, suggesting that NS5 is imported into the nucleus where it
might co-localise and interact with proteins such as the viral RNA dependent
RNA polymerase (RdRp) at sites of active viral RNA synthesis. Second,
overexpressed ZIKV NS5 co-localises with (overexpressed) STAT2 in a region that
corresponds with the ER, suggesting that the ER stress might be involved in the
degradation. Third, a subset of Vero cells expressing ZIKV NS5 exhibits
aberrant mitosis reminiscent to those observed in Vero cells expressing the coronaviral
N protein, which is characterised by the presence of a cleavage furrow. <span style="mso-spacerun: yes;"> </span>The activation of STAT2 has been shown to
promote neuronal differentiation in human left cerebrum which includes the
development of the visual perception. Since foetal ZIKV infection has been
associated with visual defects, it might be possible that ZIKV mediated
degradation of STAT2 not only abrogates type I IFN dependent signalling but
also interferes with differentiation of neuronal cells, in particular those
related to visual perception. <o:p></o:p></span></div>
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<span style="font-family: "helvetica"; mso-ansi-language: EN-US;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In conclusion, the past months saw tremendous progress
in the development of mouse models allowing closer examination of the link of
maternal ZIKV infection and the development of microcephaly due to abnormal
development of the foetal brain in offspring. With the exception of one study,
all of the models successfully employed involved the use of immunodeficient
mice suggesting that the passage of ZIKV through the maternal placenta in
immunocompetent animals is prevented in most circumstances. In addition to the
animal model, studies using human neural progenitor cells and brain organoids
suggest that in ZIKV infected cells the expression of genes controlling the
cell cycle and inhibiting apoptosis is downregulated, data that are confirmed
in transcriptome analysis of foetal brains of infected mice pups. In general
however the decrease of genes expression is more pronounced in experimentally
infected hNPC than in foetal brain which is probably due to antiviral
signalling pathways that restrict the initial infection of embryonal cells <i style="mso-bidi-font-style: normal;">in vivo</i>. </span><span style="font-family: "helvetica";"><o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=587&rft.epage=90&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=587&rft.epage=90&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u>Further reading</u></span></span></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=587&rft.epage=90&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=587&rft.epage=90&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u><br /></u></span></span></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=587&rft.epage=90&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=587&rft.epage=90&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="text-align: start;">Wang L, Valderramos SG, Wu A, Ouyang S, Li C, Brasil P, Bonaldo M, Coates T, Nielsen-Saines K, Jiang T, Aliyari R, & Cheng G (2016). From Mosquitos to Humans: Genetic Evolution of Zika Virus. </span><span style="font-style: italic;">Cell host & microbe, 19</span><span style="text-align: start;"> (5), 561-5 PMID: </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/27091703" rev="review" style="text-align: start;">27091703</a></span></span></span></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=587&rft.epage=90&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span></span>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=18&rft.issue=5&rft.spage=587&rft.epage=90&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, Yao B, Shin J, Zhang F, Lee EM, Christian KM, Didier RA, Jin P, Song H, & Ming GL (2016). Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. </span><span style="font-style: italic;">Cell stem cell, 18</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> (5), 587-90 PMID: </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/26952870" rev="review">26952870</a></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Annals+of+clinical+microbiology+and+antimicrobials&rft_id=info%3Apmid%2F26939897&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+expanding+spectrum+of+modes+of+transmission+of+Zika+virus%3A+a+global+concern.&rft.issn=&rft.date=2016&rft.volume=15&rft.issue=&rft.spage=13&rft.epage=&rft.artnum=&rft.au=Rodriguez-Morales+AJ&rft.au=Bandeira+AC&rft.au=Franco-Paredes+C&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Annals+of+clinical+microbiology+and+antimicrobials&rft_id=info%3Apmid%2F26939897&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+expanding+spectrum+of+modes+of+transmission+of+Zika+virus%3A+a+global+concern.&rft.issn=&rft.date=2016&rft.volume=15&rft.issue=&rft.spage=13&rft.epage=&rft.artnum=&rft.au=Rodriguez-Morales+AJ&rft.au=Bandeira+AC&rft.au=Franco-Paredes+C&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Rodriguez-Morales AJ, Bandeira AC, & Franco-Paredes C (2016). The expanding spectrum of modes of transmission of Zika virus: a global concern. <span style="font-style: italic;">Annals of clinical microbiology and antimicrobials, 15</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26939897" rev="review">26939897</a></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F23408610&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Nuclear+localization+of+dengue+virus+nonstructural+protein+5+does+not+strictly+correlate+with+efficient+viral+RNA+replication+and+inhibition+of+type+I+interferon+signaling.&rft.issn=0022-538X&rft.date=2013&rft.volume=87&rft.issue=8&rft.spage=4545&rft.epage=57&rft.artnum=&rft.au=Kumar+A&rft.au=B%C3%BChler+S&rft.au=Selisko+B&rft.au=Davidson+A&rft.au=Mulder+K&rft.au=Canard+B&rft.au=Miller+S&rft.au=Bartenschlager+R&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Kumar A, Bühler S, Selisko B, Davidson A, Mulder K, Canard B, Miller S, & Bartenschlager R (2013). Nuclear localization of dengue virus nonstructural protein 5 does not strictly correlate with efficient viral RNA replication and inhibition of type I interferon signaling. <span style="font-style: italic;">Journal of virology, 87</span> (8), 4545-57 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/23408610" rev="review">23408610</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> <span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Virology&rft_id=info%3Adoi%2F10.1128%2FJVI.01982-05&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Nuclear+Localization+of+Flavivirus+RNA+Synthesis+in+Infected+Cells&rft.issn=0022-538X&rft.date=2006&rft.volume=80&rft.issue=11&rft.spage=5451&rft.epage=5464&rft.artnum=http%3A%2F%2Fjvi.asm.org%2Fcgi%2Fdoi%2F10.1128%2FJVI.01982-05&rft.au=Uchil%2C+P.&rft.au=Kumar%2C+A.&rft.au=Satchidanandam%2C+V.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Uchil, P., Kumar, A., & Satchidanandam, V. (2006). Nuclear Localization of Flavivirus RNA Synthesis in Infected Cells <span style="font-style: italic;">Journal of Virology, 80</span> (11), 5451-5464 DOI: <a href="http://dx.doi.org/10.1128/JVI.01982-05" rev="review">10.1128/JVI.01982-05</a></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Virology&rft_id=info%3Adoi%2F10.1016%2Fj.virol.2015.02.033&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ubiquitination+in+the+antiviral+immune+response&rft.issn=00426822&rft.date=2015&rft.volume=479-480&rft.issue=&rft.spage=52&rft.epage=65&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0042682215000793&rft.au=Davis%2C+M.&rft.au=Gack%2C+M.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Virology&rft_id=info%3Adoi%2F10.1016%2Fj.virol.2015.02.033&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ubiquitination+in+the+antiviral+immune+response&rft.issn=00426822&rft.date=2015&rft.volume=479-480&rft.issue=&rft.spage=52&rft.epage=65&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0042682215000793&rft.au=Davis%2C+M.&rft.au=Gack%2C+M.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Davis, M., & Gack, M. (2015). Ubiquitination in the antiviral immune response <span style="font-style: italic;">Virology, 479-480</span>, 52-65 DOI: <a href="http://dx.doi.org/10.1016/j.virol.2015.02.033" rev="review">10.1016/j.virol.2015.02.033</a></span></div>
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<br />thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-23708958821654683942016-05-11T15:25:00.000-04:002016-05-11T22:26:56.994-04:00ZIKV infection of brain organoids: role of TLR-3 induced apoptosis due to changes in gene expression?<div class="MsoNormal" style="text-align: justify;">
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<span lang="EN-GB"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Circulating ZIKV strains can be separated into
two clades, African and Asiatic with the former comprised of two groups (MR766
and the Nigerian cluster) and the latter into the Malaysian and Micronesian
strain although the genetic diversity is rather low ( less than 12 % between
the African and Asian clades). <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span lang="EN-GB">ZIKV is transmitted by mosquitoes and can be
readily isolated from Aedes mosquitoes in Africa (including <i style="mso-bidi-font-style: normal;">Ae. Furcifer, Ae. </i></span><i style="mso-bidi-font-style: normal;">luteocephalus</i>,<i style="mso-bidi-font-style: normal;"> Ae. taylori,
Ae. dalzieli</i>,<i style="mso-bidi-font-style: normal;"> Ae. opok, Ae. vittatus</i>,<i style="mso-bidi-font-style: normal;"> Ae. jamoti</i>,<i style="mso-bidi-font-style: normal;"> Ae. flavicollis, Ae. graham</i>i,<i style="mso-bidi-font-style: normal;">
Ae. taeniarostris</i>,<i style="mso-bidi-font-style: normal;"> Ae. tarsalis</i>,<i style="mso-bidi-font-style: normal;"> Ae. fowleri, Ae. metallicus</i>,<i style="mso-bidi-font-style: normal;"> Ae. minutus</i>,<i style="mso-bidi-font-style: normal;"> Ae. neoafricanus, Ae. Albopictus</i><span lang="EN-GB">) as well as from Anopheles mosquitoes (</span><i style="mso-bidi-font-style: normal;">An. coustani</i>, <i style="mso-bidi-font-style: normal;">An. gambiae</i>),
Mansonia (<i style="mso-bidi-font-style: normal;">Ma. uniformis</i>) and Culex (<i style="mso-bidi-font-style: normal;">Cx. Perfuscus</i>) whereas in Asia ZIKV is
transmitted by <i style="mso-bidi-font-style: normal;">Aedes aegypti</i>.
Mosquitoes are not however the primary host for ZIKV. Both in Africa and Asia,
non-human primates have been proposed to be the reservoir for ZIKV with forest
dwelling mosquitoes transmitting ZIKV to humans. Once established within the
human population, ZIKV is transmitted by mosquitoes as well horizontally by
sexual intercourse, vertical and parenteral. <span style="mso-spacerun: yes;"> </span><o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">During the current outbreak of ZIKV in Brazil, ZIKV
RNA was detected in amniotic fluid samples of women infected with ZIKV during
pregnancy and ZIKV RNA has also been isolated from tissue (brain and CNS) of
neonates born with microcephaly, suggesting that ZIKV infection of the mother
might be a contributive factor in the observed increase of microcephaly cases
in neonates. In addition to microcephaly, miscarriages have also been reported
in ZIKV positive pregnant women, especially during the first trimester of
pregnancy. Foetal deaths have been observed in women who were infected with
ZIKV during the second and third trimester in addition to neonate death within
20 hrs following birth. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In addition to miscarriages, foetal and neonatal
death, (congenital) ocular findings associated with microcephaly have been
reported in 34.5% of infants examined that lead to eye damage. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In principle, teratogenic effects following viral
infection of pregnant women is well documented for other viruses such as Herpes
Virus simplex or Rubella Virus (RV). In the case of RV, the cytopathogenesis of
infected foetal tissues suggests that RV infection of the foetus in utero
induces extensive apoptosis and necrosis as well as mitotic defects of
precursor cells, thus leading to abnormal organogenesis. These results are
supported by results obtained in WI-38 human diploid fibroblasts showing that
the viral 33A protein inhibits mitosis and the expression of the viral Capsid
protein and all three structural proteins (but not the E1 or E2 protein
separately) in RK13 cells induces apoptosis, is independent of the
mitochondrial pathway probably as a result of the induction of the ER stress
response. <o:p></o:p></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In the case of ZIKV, apoptosis of precursor cells
especially of neural progenitor cells, has been demonstrated for brain
organoids as well as human progenitor stem cells (hNPC) as discussed
previously. Foetal infection during the early stages however requires viral
particles to cross the placental barrier. In the case of ZIKV, the expression
of Interferon-<span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">l</span> (IFN-<span style="mso-char-type: symbol; mso-symbol-font-family: Symbol;">l</span>) in trophoblasts may
limit ZIKV replication and thus the ability to infect embryonal or foetal
cells. A recent paper however showed that at least in a small number of
infection acquired microcephaly the maternal placenta allows the passage of
infected Hofbauer cells since maternal histiocytes-immune cells of monocyte
origin- are frequently found within the human placenta, have the ability to
reach foetal vessels and and subsequently infect neuronal precursor cells, thus
causing neuronal abnormalities associated with microcephaly and/or ocular
abnormalities. Transplacental passage of infected histiocytes has been reported
for other viral diseases, including seasonal (A/H1N1) influenza where the
infection in early pregnancy caused second trimester foetal demise.<o:p></o:p></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The notion that ZIKV can cause microcephaly is further supported by recent findings that in female Ifnar1 -/- as well as in wt mice treated with an inhibitor (MAR1-5A3)against Ifnar1, foetuses exhibit symptoms similar to those observed in infants born to ZIKV positive mothers that exhibit microcephaly. Viral RNA could be detected in the foetal brain of infected mice up to 16.5 days during embryonal development as well as in the placenta, suggesting that in Ifnar1 -/- mice ZIKV not only replicates in the placenta but also crosses the placenta and thus infects the embryo.</span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span lang="EN-GB">Research on ZIKV pathogenesis currently underway
utilises cell lines, animal models and brain organoids, which are used to study
the various aspects of the interaction of ZIKV with the host cell. ZIKV
research thus benefits from both “traditional” (cell lines and animal models)
as well as “modern” advances in cell biology. Whereas cell lines and animal
models are used for a long time to study virus-host interactions, the use of
hNPC and brain organoids is a relatively modern development. Brain organoids were
developed to study neurodegenerative disorders and are stem cells and are </span>human iPSC-derived neural
progenitor cells (NPCs) that have differentiated into 3D organoid systems epitomize
forebrain, midbrain, and hindbrain regions and thus represent a model of the
developing brain. <o:p></o:p></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The infection of mouse neurospheres as well as 10-day
old human immature cerebral organoids with ZIKV MR766 exhibited a significant
decrease in growth compared to mock infected samples as early as 24 hrs p.i. as
well as viral replication, indicating that ZIKV indeed does decrease growth of
brain organoids which has been shown to be due to the induction of apoptosis. The
induction of apoptosis can be due to the downregulation of genes that inhibit
apoptosis induced by a variety of processes including DNA damage, aberrant cell
division or mitochondrial depolarisation as has been proposed ZIKV infection of hNPC or due to downregulation of genes regulating the aforementioned processes as a result of ZIKV induced antiviral signalling. Alternatively, ZIKV proteins and/or viral RNA (both dsRNA intermediates and ss genomic RNA) may activate the apoptotic response. </span><br />
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<tr><td style="text-align: center;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhN7nHYavz35wSH1bzTMfQzrGY_W9guBQ1DIdA_TT2q9o5FjXNFWeBz44r0rltjZtj1b9hMYyemvYoGLwvVJ4riVBozRyRM1xGVURLNZm_LSA8G6f5174wenrRf44vX-04AR3XB2-xJTyDM/s640/ZIKV+in+organoids.001.jpeg" style="margin-left: auto; margin-right: auto;" width="640" /></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><br /></td></tr>
</tbody></table>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhCASGtQun8pZ7rVyjMMSfbi_XZNmrYFocm0PsxrWhTLnq5ICXIjwggpn-WP4s2lPqN6Zc0hO1TjXLHZheWu3JkHIxyAWRago4Mwkmm22No4MTFhNtnrbmVL4YeOP1tRLlngNexxMYRHaCV/s1600/ZIKV+in+organoids.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhCASGtQun8pZ7rVyjMMSfbi_XZNmrYFocm0PsxrWhTLnq5ICXIjwggpn-WP4s2lPqN6Zc0hO1TjXLHZheWu3JkHIxyAWRago4Mwkmm22No4MTFhNtnrbmVL4YeOP1tRLlngNexxMYRHaCV/s640/ZIKV+in+organoids.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Downregulation of gene groups in brain organoids compared to neural<br />
stem cells</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">ZIKV infection of brain organoids,
hNPC and A549 cells has been reported to induce caspase dependent apoptosis
probably via the mitochondrial pathway which may be associated with the
downregulation of genes associated with DNA replication and mitosis.
Interestingly, human brain organoids exhibit a downregulation of in the
expression of genes related to DNA replication, cell cycle progression, mitosis
and apoptosis compared to human neuronal stem cells raising the possibility
that brain organoids may be more sensitive to viral induced modulation of gene
expression or to the induction of apoptosis by viral proteins and/or viral RNA; regrettably, as of now no data are available that compare the
transcriptome of ZIKV infected neuronal stem cells with the transcriptome of
ZIKV infected cell lines and brain organoids which may indicate whether ZIKV infection does indeed modulate the expression of genes similar to infected hNPC cells or not. </span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In any case, the infection of cell lines and brain
organoids with ZIKV as well as treatment with Poly (I:C) induces TLR-3 mediated
antiviral signalling and subsequent apoptosis which can partially reversed by
treatment of organoids with a TLR-3 inhibitor. </span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">These data indicate that ZIKV
infection may trigger apoptosis of foetal brain cells during the first trimester of foetal development
and thus contributes to the malformation of the brain associated with
microcephaly. In addition, Poly (I:C) induced TLR-3 signalling also
downregulates the expression of two genes related to neurogenesis, Nestrin and <span style="color: #424242;">Ephrin
type-B receptor 2, both of which are also downregulated in ZIKV infected hNPC, suggesting that ZIKV indeed impairs neural development.<o:p></o:p></span></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="color: #424242;"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="color: #424242;"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="color: #424242;"><br /></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="color: #424242;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Interestingly, the
expression of UNC93B1 is downregulated both in primary human trophoblasts
(compared to JEG-3 cells) and in cerebral organoids (compared to hNPC). In
humans, UNC9393B1 deficiency has been linked to predispose patients to HSV
encephalitis that causes severe neurological damage. In mice, point mutations
of UNC93B1 have been linked to prevent TLR-3 (as well as TLR-7 and -9)
localisation to the endolysosomal compartment that contain the ligand and thus
prevent activation of TLR mediated signaling pathways. If UNC93B1 deficiency
contributes to ZIKV induced pathogenesis –not only in the developing foetus but
also in adult patients- is not clear and needs to be investigated. <o:p></o:p></span></span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgn9Ot2joQ3YTqKxEjEV7NR0tiBZdS20R88dI2kx5hKFtvVPBd0euip2rCt2aC6YFo3qbrVx59uDS_EDaKsYFoo9ykkR-uT05H70rbR_lYt85Gye-3fG1buq1VOcszy-Flmav3Fd18KRrc2/s1600/ZIKV+in+organoids.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgn9Ot2joQ3YTqKxEjEV7NR0tiBZdS20R88dI2kx5hKFtvVPBd0euip2rCt2aC6YFo3qbrVx59uDS_EDaKsYFoo9ykkR-uT05H70rbR_lYt85Gye-3fG1buq1VOcszy-Flmav3Fd18KRrc2/s640/ZIKV+in+organoids.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Downregulation of UNC93B1 in ZIKV infected hNPC and non-infected <br />
brain organoids </td></tr>
</tbody></table>
<span style="color: #424242;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span style="color: #424242;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span style="color: #424242;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span style="color: #424242;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span style="color: #424242;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Both viral RNA and Poly (I:C) has been shown to induce
apoptosis by activating both caspase-3 and caspase-8 dependent pathways through
TLR-3 and ZIKV has been shown to induce apoptosis in both brain organoids and hNPC
neuronal cells as well as in A549 cells. Interestingly, in ZIKV infected hNPC
the expression of XIAP (X-linked inhibitor pf apoptosis) is upregulated,
suggesting that ZIKV might be able to inhibit caspase-3 dependent apoptosis in
hNPC. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Pending further studies, activation of TLR-3 by ZIKV
RNA (dsRNA intermediate and/or genomic ssRNA) might induce the degradation of
the TLR-3/RNA complex via the formation of autophagosomes and subsequent fusion
of the autophagosome with the lysosome. Alternatively –or additionally- viral
RNA located in early endosomes might be degraded following the fusion of the
late endosome with the lysosome. Deficiency of UNC93B1 in brain organoids
therefore would prevent the degradation of ZIKV RNA by autophagy and therefore
promote viral replication. <o:p></o:p></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyNa-Fj5Kw1uErrS0BSbe82DviO0B7eE20SD94q5kDwqiIW2dapcsjKXDsMUeJkTG6YeSkgU8X50gDK7hG1qJtRmNjno8KI_FtLTUKh-DBUx1RaWr0lF5tBG78NVUtrFPWM5bgsNCneN5H/s1600/ZIKV+in+organoids.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyNa-Fj5Kw1uErrS0BSbe82DviO0B7eE20SD94q5kDwqiIW2dapcsjKXDsMUeJkTG6YeSkgU8X50gDK7hG1qJtRmNjno8KI_FtLTUKh-DBUx1RaWr0lF5tBG78NVUtrFPWM5bgsNCneN5H/s640/ZIKV+in+organoids.006.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: TLR-3 is degraded in a UNC93B1 dependent manner upon binding to viral RNA</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<br /></div>
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<br /></div>
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<br /></div>
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<br /></div>
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<br /></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="color: #424242;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In conclusion, ZIKV
might cross the placenta not by infecting placental cells but by migration of
infected Hofbauer cells and subsequent infection of neuronal precursor cells
followed by activation of TLR-3 dependent signalling pathways that induce both
apoptosis and decrease the expression of genes related to neurogenesis. A
recent study identified long noncoding RNAs (lncRNAs) that suppress the
interferon response in human trophectoderm and primitive endoderm cells,
suggesting that the expression of lncRNA in hNPC and brain organoids might
contribute to ZIKV infection and ZIKV induced apoptosis. So far however this
has not been investigated whereas the activation of TLR-3 has been shown to be involved
in perinatal brain injury. </span></span><span style="color: #424242; font-family: "helvetica"; font-size: 13.0pt;"><o:p></o:p></span><br />
<br /></div>
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<br /></div>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"></span><br />
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u>Further reading </u></span></span><br />
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-size: large;"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Brazilian+journal+of+medical+and+biological+research+%3D+Revista+brasileira+de+pesquisas+medicas+e+biologicas+%2F+Sociedade+Brasileira+de+Biofisica+...+%5Bet+al.%5D&rft_id=info%3Apmid%2F27143174&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Overview+of+Zika+virus+%28ZIKV%29+infection+in+regards+to+the+Brazilian+epidemic.&rft.issn=0100-879X&rft.date=2016&rft.volume=49&rft.issue=5&rft.spage=&rft.epage=&rft.artnum=&rft.au=Slavov+SN&rft.au=Otaguiri+KK&rft.au=Kashima+S&rft.au=Covas+DT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Slavov SN, Otaguiri KK, Kashima S, & Covas DT (2016). Overview of Zika virus (ZIKV) infection in regards to the Brazilian epidemic. <span style="font-style: italic;">Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.], 49</span> (5) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27143174" rev="review">27143174</a></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></span></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Immunological+reviews&rft_id=info%3Apmid%2F26683145&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Nucleic+acid-sensing+TLRs+and+autoimmunity%3A+novel+insights+from+structural+and+cell+biology.&rft.issn=0105-2896&rft.date=2016&rft.volume=269&rft.issue=1&rft.spage=60&rft.epage=75&rft.artnum=&rft.au=Pelka+K&rft.au=Shibata+T&rft.au=Miyake+K&rft.au=Latz+E&rfe_dat=bpr3.included=1;bpr3.tags=">Pelka K, Shibata T, Miyake K, & Latz E (2016). Nucleic acid-sensing TLRs and autoimmunity: novel insights from structural and cell biology. <span style="font-style: italic;">Immunological reviews, 269</span> (1), 60-75 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26683145" rev="review">26683145</a></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+Reviews+Neurology&rft_id=info%3Adoi%2F10.1038%2Fnrneurol.2015.13&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+role+of+inflammation+in+perinatal+brain+injury&rft.issn=1759-4758&rft.date=2015&rft.volume=11&rft.issue=4&rft.spage=192&rft.epage=208&rft.artnum=http%3A%2F%2Fwww.nature.com%2Fdoifinder%2F10.1038%2Fnrneurol.2015.13&rft.au=Hagberg%2C+H.&rft.au=Mallard%2C+C.&rft.au=Ferriero%2C+D.&rft.au=Vannucci%2C+S.&rft.au=Levison%2C+S.&rft.au=Vexler%2C+Z.&rft.au=Gressens%2C+P.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions%2C+Molecular+Biology">Hagberg, H., Mallard, C., Ferriero, D., Vannucci, S., Levison, S., Vexler, Z., & Gressens, P. (2015). The role of inflammation in perinatal brain injury <span style="font-style: italic;">Nature Reviews Neurology, 11</span> (4), 192-208 DOI: <a href="http://dx.doi.org/10.1038/nrneurol.2015.13" rev="review">10.1038/nrneurol.2015.13</a></span> </span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Molecular+and+cellular+biology&rft_id=info%3Apmid%2F27066803&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=LNCRHOXF1%3A+a+long+noncoding+RNA+from+the+X-chromosome+that+suppresses+viral+response+genes+during+development+of+the+early+human+placenta.&rft.issn=0270-7306&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Penkala+I&rft.au=Wang+J&rft.au=Syrett+CM&rft.au=Goetzl+L&rft.au=L%C3%B3pez+CB&rft.au=Anguera+MC&rfe_dat=bpr3.included=1;bpr3.tags=">Penkala I, Wang J, Syrett CM, Goetzl L, López CB, & Anguera MC (2016). LNCRHOXF1: a long noncoding RNA from the X-chromosome that suppresses viral response genes during development of the early human placenta. <span style="font-style: italic;">Molecular and cellular biology</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27066803" rev="review">27066803</a></span></div>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-53179196391194424952016-05-04T18:11:00.002-04:002016-05-04T18:19:02.507-04:00Zika Virus pathogenesis in adult mice: comparison to SINV ?<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Zika Virus (ZIKV) is a mosquitoe born member of the <i>Flaviviridae </i>which was (initially)
isolated in 1947 from a sentinel rhesus macaque monkey in Uganda. Although being
reported in humans in Uganda and Tanzania, ZIKV was reported only to cause
sporadic infections in Africa and Southeast Asia. Since 2007 however major
outbreaks have been reported in Yap/Micronesia (2007), French Polynesia
(2013-2014) and most recently in the Caribbean and South America, where ZIKV
was introduced as early as 2014. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Until recently, clinical manifestations of ZIKV
infection ranged from asymptomatic infections to mild dengue-like symptoms
characterised by mild fever, rash, muscle/joint pain and headache. Following
the 2007 epidemic however neurological complications following ZIKV infection
including Guillan-Barre Syndrome (GBS) have been reported and during the
current outbreak, ZIKV has been implicating to cause microcephaly and ocular
malformations in foetuses born to ZIKV positive mothers. In the absence of a
suitable animal model however an association between ZIKV infection and (foetal) neurological anomalies has not been definitively proven although the infection
of both brain organoids and human neural precursor cells (hNPC) with ZIKV
induces apoptosis, thus suggesting that ZIKV might cause neuronal anomalies in
the foetus by inducing apoptosis. Since placental cells however probably <a href="http://virologytidbits.blogspot.com/2016/04/zikv-pathogenesis-development-of-animal.html" target="_blank">do notsupport viral replication</a> the mode of transmission is still elusive. The
connection between ZIKV infection and neuronal anomalies is further complicated
by the co-circulation of other viruses such Dengue Virus (DENV) that may
enhance ZIKV replication or the severity of symptoms. Indeed, antibody-dependent
enhancement (ADE) has been observed in humans as a result of a previous exposure
to DENV after which antibodies against the structural precursor-membrane
protein (prM) promote ADE following infection with a different DENV serotype.
Whether this also increases the severity of ZIKV (particular of the Asian
lineage) remains to be seen.<o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">These and other questions however underline the
necessity for an animal model.<o:p></o:p></span></div>
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<b style="mso-bidi-font-weight: normal;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="mso-spacerun: yes;"> </span>ZIKV
animal model: AG129 mice <o:p></o:p></span></b></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">As described before, early experiments dating back to
the early 1950s suggested that in mice infected with ZIKV do not succumb to
ZIKV if infected with a strain directly isolated from monkeys or passaged in
C6/36 mosquitoe cells. In contrast, a mouse adapted strain causes severe
disease including paralysis and subsequent death. In general, the severity of
the disease is age dependent in so far as younger mice are more susceptible to
ZIKV infection compared to older mice. Further experiments showed that ZIKV
suspensions injected intracerebrally cause neuronal apoptosis both within the
brain and CNS, suggesting that ZIKV induced paralysis might be due to apoptosis
of neuronal cells. In principle, these results were confirmed by <i style="mso-bidi-font-style: normal;">in vitro</i> studies using brain organoids
and hNPC.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">More recently, <span lang="EN-GB">triple knockout (TKO) IRF3 -/- IRF5 -/- IRF7 -/-
mice infected with ZIKV exhibited symptoms such as paralysis as early as 3 days
p.i and up to 100% of infected TKO mice were dead 10 days p.i., suggesting that
the antiviral interferon response induced by ZIKV is limiting the severity of
the disease. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span lang="EN-GB">These findings are supported by observations in
AG129 mice that are deficient for Interferon (IFN)-α /-β/-</span><span lang="EN-GB"> </span><span lang="EN-GB">γ<span style="mso-spacerun: yes;"> </span>and have been infected with a strain isolated
from a traveller to French Polynesia (ZIKV H/PF/2013) either by foot pad (f.p.)
or intraperitoneal (i.p.) injection. In this case, both young (3-4 week old)
and adult (8 week old) mice exhibited symptoms as early as day 4 p.i. and had
to be sacrificed at day 7 p.i. (young mice) and day 8 p.i. respectively. In contrast
to earlier observations made in mice infected with a mouse adapted ZIKV 766
variant strain, infection of mice with ZIKV H/PF/2013 did not cause paralysis
but only became weak, immobile and exhibited rapid weight loss. Highest viral
titres were observed in the brain of infected mice which is in accordance with
previously published results indicating that ZIKV MP1751 replicates well in
astroglial and neuronal cells of infected mice. Both young and adult AG129 mice
exhibited similar viral titres suggesting that in the absence of antiviral
signalling, the age of mice is not relevant. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-GB"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In accordance with previously published results
high viral titres can also be detected in other tissues such as the heart,
liver, spleen, kidney, and muscle suggesting that ZIKV can replicate in these
tissues. In accordance with previous results, histopathological examination of
brain tissue of infected mice revealed extensive cell death (pyknosis and necrosis)
as well as infiltration of neutrophils, suggesting that ZIKV indeed causes
severe brain pathology in AG129 mice.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<br /></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-GB"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In causing a more severe disease in young mice
compared to adult mice, mouse adapted ZIKV resembles other neuropathogenic
viruses, such as Sindbis Virus (SINV). In the case of SINV, wt SINV is virulent
only for neonatal mice but not weanling mice. Similar to ZIKV, SINV passaged in
mouse brain increases neuroinvasiveness in adult mice which is due to two amino
acid changes in the E2 protein (His55 to Gln and Glu70 to Lys in one isolate
and Lys190 to Met and Glu260 to Lys in a second isolate); if mice adapted ZIKV
strains also exhibit similar changes that increase viral entry or counteract
the antiviral response has not been demonstrated yet. Age dependent
neurovirulence of SINV however has been demonstrated to be due to apoptosis
induced by the viral E2 protein, in particular dependent on the His55 to Gln
amino acid change. Additionally, the expression of IRF-3 and IRF-7 in mature
(differentiated) rat AP-7 neurons has been linked to decreased mortality in adult
mice although other factors such as a better antibody response resulting in
rapid clearance of SINV mediated by Interleukin-10 may also influence survival
rates. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-GB"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Again, in the case of ZIKV more studies using
animal models are needed, involving the use of mice adapted ZIKV strains. Using
a mouse model might also assist in determining the teratogenic effect of ZIKV,
determine the role of co-infection with DENV and assist the development of a
vaccine.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></span></div>
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padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=M%C3%A9decine+et+Maladies+Infectieuses&rft_id=info%3Adoi%2F10.1016%2Fj.medmal.2014.04.008&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Current+Zika+virus+epidemiology+and+recent+epidemics&rft.issn=0399077X&rft.date=2014&rft.volume=44&rft.issue=7&rft.spage=302&rft.epage=307&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0399077X14001085&rft.au=Ioos%2C+S.&rft.au=Mallet%2C+H.&rft.au=Leparc+Goffart%2C+I.&rft.au=Gauthier%2C+V.&rft.au=Cardoso%2C+T.&rft.au=Herida%2C+M.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u>Further reading</u></span><br />
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=M%C3%A9decine+et+Maladies+Infectieuses&rft_id=info%3Adoi%2F10.1016%2Fj.medmal.2014.04.008&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Current+Zika+virus+epidemiology+and+recent+epidemics&rft.issn=0399077X&rft.date=2014&rft.volume=44&rft.issue=7&rft.spage=302&rft.epage=307&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0399077X14001085&rft.au=Ioos%2C+S.&rft.au=Mallet%2C+H.&rft.au=Leparc+Goffart%2C+I.&rft.au=Gauthier%2C+V.&rft.au=Cardoso%2C+T.&rft.au=Herida%2C+M.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+neglected+tropical+diseases&rft_id=info%3Apmid%2F27093158&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Characterization+of+Lethal+Zika+Virus+Infection+in+AG129+Mice.&rft.issn=1935-2727&rft.date=2016&rft.volume=10&rft.issue=4&rft.spage=&rft.epage=&rft.artnum=&rft.au=Aliota+MT&rft.au=Caine+EA&rft.au=Walker+EC&rft.au=Larkin+KE&rft.au=Camacho+E&rft.au=Osorio+JE&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Aliota MT, Caine EA, Walker EC, Larkin KE, Camacho E, & Osorio JE (2016). Characterization of Lethal Zika Virus Infection in AG129 Mice. <span style="font-style: italic;">PLoS neglected tropical diseases, 10</span> (4) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27093158" rev="review">27093158</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F27028153&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Molecular+Determinants+of+Alphavirus+Neuropathogenesis+in+Mice.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Atkins+GJ&rft.au=Sheahan+BJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Atkins GJ, & Sheahan BJ (2016). Molecular Determinants of Alphavirus Neuropathogenesis in Mice. <span style="font-style: italic;">The Journal of general virology</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27028153" rev="review">27028153</a></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Lancet+%28London%2C+England%29&rft_id=info%3Apmid%2F26952548&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Teratogenic+effects+of+the+Zika+virus+and+the+role+of+the+placenta.&rft.issn=0140-6736&rft.date=2016&rft.volume=387&rft.issue=10027&rft.spage=1587&rft.epage=90&rft.artnum=&rft.au=Adibi+JJ&rft.au=Marques+ET+Jr&rft.au=Cartus+A&rft.au=Beigi+RH&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Adibi JJ, Marques ET Jr, Cartus A, & Beigi RH (2016). Teratogenic effects of the Zika virus and the role of the placenta. <span style="font-style: italic;">Lancet (London, England), 387</span> (10027), 1587-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26952548" rev="review">26952548</a></span> </span></div>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-71552938860654167272016-04-28T17:33:00.001-04:002016-04-29T17:37:38.100-04:00MERS-CoV and antiviral singling: role of orf4b and M protein<span style="float: left; padding: 5px;"></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F25810418&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Middle+East+respiratory+syndrome+coronavirus%3A+another+zoonotic+betacoronavirus+causing+SARS-like+disease.&rft.issn=0893-8512&rft.date=2015&rft.volume=28&rft.issue=2&rft.spage=465&rft.epage=522&rft.artnum=&rft.au=Chan+JF&rft.au=Lau+SK&rft.au=To+KK&rft.au=Cheng+VC&rft.au=Woo+PC&rft.au=Yuen+KY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"></span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;">Coronaviruses (CoV)
are positive sense RNA viruses with a genome size of 29-32 kb with four genera
(Alpha-, Beta-, Gamma- and Delta CoV) belonging to the family of the <i style="mso-bidi-font-style: normal;">Coronaviridae</i> within the order of <i style="mso-bidi-font-style: normal;">Nidovirales</i>, with the Betacoronaviruses
further divided into four lineages (A-D). <o:p></o:p></span><br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjL88RyJim4ezG9oGeteLjjJyKFXgIPxz8T23S1SsN6lgDLSffcZ3fEPm1-XEK_ppTC5m148LGO-HstbAFou2F7GOEaej4qhnI1VYPFrt4yZAvB9kwS0BiqbhfF7fshAJBbJKuMxMWU4HH6/s1600/Blog+MERS+update.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjL88RyJim4ezG9oGeteLjjJyKFXgIPxz8T23S1SsN6lgDLSffcZ3fEPm1-XEK_ppTC5m148LGO-HstbAFou2F7GOEaej4qhnI1VYPFrt4yZAvB9kwS0BiqbhfF7fshAJBbJKuMxMWU4HH6/s640/Blog+MERS+update.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Table: Classification of known CoV</span></td></tr>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;">Most CoV identified
until now are causing severe disease only in animals including agricultural
important animals such as chicken, cattle, and pigs. To date only six human CoV
(HCoV) have been identified, namely HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1,
Severe Respiratory Syndrome (SARS)-CoV and most recently Middle Eastern
Respiratory Syndrome (MERS)-CoV, although a SARS-like CoV, WIV1-CoV, replicates
in primary human epithelial cells at low levels as well as in mice expressing
the human SARS-CoV receptor ACE2 albeit at lower levels compared to
SARS-CoV.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;">In contrast to
SARS-CoV and MERS-CoV, the infection with HCoV-229E, HCoV-OC43, HCoV-NL63 and
HCoV-HKU1only causes mild upper respiratory tract infections, whereas the
infection with MERS-CoV causes severe lower respiratory infection and renal
failure which may lead to the death of infected individuals. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;">Although the natural
host for MERS-CoV has not been conclusively identified, bats might act as a
natural reservoir of MERS-CoV (similar to Hendra and Nipah Virus) as evidenced
by studies indicating the presence of MERS-like CoV in bats from Saudi Arabia,
Europe, Africa and Asia. Furthermore, MERS-CoV can enter and replicate both in
cell lines derived from bats and humans and the closely related Bat CoV-HKU4
can enter cells by binding to DPP4, the receptor for MERS-CoV. In Jamaican
fruit bats (<i style="mso-bidi-font-style: normal;">Artibeus jamaicensis</i>)
experimentally infected with MERS-CoV, clinical signs are absent despite viral
replication and shedding in the respiratory and intestinal tract for up to 9
days p.i. as well as the induction of an antiviral response (see below for
discussion).<o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;">Despite the ability of
MERS and MERS-like CoV to infect both human and bat cell lines, bats are
unlikely to be the source for the current outbreak of MERS in the Arabian
Peninsula based on findings that livestock –in particular dromedary camels-
have a high seroprevalence for MERS-CoV. In addition, recent studies showed
that DPP4 is expressed at high levels in the upper respiratory tract of
dromedary camels (but not humans) and that sequences of MERS-CoV isolated from
dromedary camels are highly similar to sequence from human derived viral
isolates. Finally, camel derived MERS-CoV can efficiently replicate in human
cells.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></div>
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<b style="mso-bidi-font-weight: normal;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;"><span style="mso-spacerun: yes;"> </span>MERS-CoV
and the Interferon response<o:p></o:p></span></b></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;">The polycistronic
single stranded positive sense viral RNA of MERS-CoV encodes for two
polyproteins, orf1a and orf1b, within the 5’ end which are cleaved into a total
of 16 non-structural proteins (nsp) including the viral RNA dependent RNA
polymerase whereas the 3’ end of the viral RNA encodes for the structural
proteins, namely spike (S), membrane (M), envelope (E) protein as well as
lineage specific proteins.<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 14.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgh7xetggt_DBHJCf-RInypV5cpopCuv_j70pv2LPj74OfWuaXqYXAYh-6ETR05xfY67iMv2W6U7tSXIeOr-D4BPIF_bFtmd47jOvn-lUmeISuw76qaSLpgYhtm5qcGMLLY9x-85-0PV3uK/s1600/Blog+MERS+update.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgh7xetggt_DBHJCf-RInypV5cpopCuv_j70pv2LPj74OfWuaXqYXAYh-6ETR05xfY67iMv2W6U7tSXIeOr-D4BPIF_bFtmd47jOvn-lUmeISuw76qaSLpgYhtm5qcGMLLY9x-85-0PV3uK/s640/Blog+MERS+update.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Figure: Processing of the orf1ab into several nsp</span></td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="line-height: 14.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;">Following viral entry
and release of the viral RNA, MERS-CoV replicates in the cytoplasm of cell,
although the viral N protein is imported into the nucleus and localizes to the
nucleolus. During viral replication, replication centers containing viral
proteins and dsRNA are formed in the ER-Golgi intermediate compartment (ERGIC)
in a process that might involve the induction of autophagy and/or viral induced
rearrangements of the ER membrane that promote the formation of vesicular
structures. <o:p></o:p></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgJYIKJ77LcMoUlW8i2D1jUct6hmAxJQHJDj1hbQQSjtmqxwqJDESutpeSXDahOWTtrvmSPAhJfJ8DKKsJW7QhCySs5vUDS-VWpeTiYDXSmVB_Hf0FE23b423gchSZZ9Q80JcGI38mQe4NJ/s1600/Blog+MERS+update.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgJYIKJ77LcMoUlW8i2D1jUct6hmAxJQHJDj1hbQQSjtmqxwqJDESutpeSXDahOWTtrvmSPAhJfJ8DKKsJW7QhCySs5vUDS-VWpeTiYDXSmVB_Hf0FE23b423gchSZZ9Q80JcGI38mQe4NJ/s640/Blog+MERS+update.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Figure: Outline of CoV replication cycle</span></td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;"><br /></span></div>
<div class="MsoNormal" style="line-height: 14.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;">The infection of a
variety of cell lines with SARS-CoV and MERS-CoV has been reported to induce
the expression of type I interferons (IFN) including IFN-α and IFN-β,
suggesting that both SARS-CoV and MERS-CoV induce antiviral signaling via the
recognition of viral RNA by PRR and PAMPS. Furthermore, both SARS-CoV and
MERS-CoV express proteins that counteract the IFN pathway and thus contribute
to the severity of infection. In general, MERS-CoV RNA is recognized by viral
sensors of the retinoic acid-inducible gene-I (RIG-1)-like receptor (RLR)
family melanoma differentiation gene 5 (MDA5) that upon activation by viral
dsRNA intermediates, induce the nuclear translocation of both IFN regulatory
factor (IRF)-3 and nuclear factor κB (NF-κB), both of which induce the
expression of IFN-β.<span style="mso-spacerun: yes;"> </span>RIG-1 signaling
induced by the viral RNA as well as by Poly (I:C) however can be inhibited by
several viral proteins, including ORF4a, ORF4b, ORF5 and M. In the case of
ORF4a, the viral protein binds dsRNA and thus inhibits the activation of RIG-1
and MDA-5, whereas the nuclear localization of ORF4b inhibits the induction of
IFN-β as well as the expression of RIG-I, MDA5, MAVS, IKKε, and TBK-1 by
inhibiting both (nuclear) IRF-3 and IRF-7 whereas in the cytoplasm ORF4b
inhibits antiviral signaling by binding to TANK binding kinase 1 (TBK1) and IκB
kinase epsilon (IKK-ε) thus suppressing the interaction between mitochondrial
antiviral signaling protein (MAVS) and IKK-ε. In addition to inhibiting IRF-3
by binding to TBK1, both MERS-CoV and ORF4b protein also inhibits antiviral
signaling by inhibiting the IFN inducible oligoadenylate synthetase (OAS)-RNase
L pathway that is activated by the viral dsRNA intermediate via degradation of 2′,5′-oligoadenylate
(2-5A), the activator of RNase L, thus inhibiting RIG-1 and MDA-5 induced
signaling. Interestingly, ORF4b localises to the nucleolus in ORF4b transfected
cells, but so far the importance for nucleolar localisation of ORF4b for
antiviral signaling has not been demonstrated. In contrast to ORF4b, ORF5 –like
ORF4a and M- can only be detected in the cytoplasm of infected cells. Similar
to ORF4b however, the expression of ORF5 inhibits the induction of IFN-β upon
infection with Sendai Virus (albeit to a lesser effect) probably by inhibiting
IRF-3 and -7 but not NF-κB. <span style="mso-spacerun: yes;"> </span><span style="color: #c00000;"><o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Activated
RNaseL cleaves viral and cellular ssRNA including ribosomal RNA preferentially
at UU and UA dinucleotide residues, therefore not only inhibiting replication
of the viral genome but also the expression of viral proteins as well as
processing viral RNA to be recognized by intracellular RNA sensing proteins
thus activating antiviral signaling pathways.<o:p></o:p></span></div>
<div class="MsoNormal" style="line-height: 14.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">I</span><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">n the case of CoV, the Mouse Hepatitis Virus
(MHV) NS2 protein encoded by ORF2a has been identified as an inhibitor of the OAS-RNaseL
pathway by inhibiting the conversion of intracellular ATP to 2’,5’- OAS via the
2’,5’ Phosphodiesterase domain (PDE) following the detection of viral dsRNA
intermediates or synthetic Poly (I:C) RNA. Alignment of MERS-CoV, BtCoV-HKU5
and BtCoV-SC2013 orf4b with MHV nsp2 lead to the identification of a 2’,5’- PDE
domain that is preceded by a nuclear localization signal that is catalytically
active in a fluorescence resonance energy transfer (FRET) based RNaseL activity
assay with similar kinetics to MHV nsp2. As expected, all orf4b proteins
localize to the nucleus and the cytoplasm if expressed in murine L2 cells
infected with MHV chimeras that express a catalytically inactive mutant of nsp2
and catalytically active orf4b derived from MERS-CoV or BatCoV-SC2013; in case
of the MHV-BtCoV-HKU5 orf4b chimera, orf4b predominantly localises to the
nucleus<span style="mso-spacerun: yes;"> </span>which does not affect viral
replication but might not inhibit the activation of RNaseL, indicating that
only cytoplasmic orf4b can inhibit RNaseL activation. In Calu-3 cells, a human
airway epithelial cell line, infected with MERS-CoV, the deletion of nsp3-5 or
the deletion of orf4b does not activate the degradation of rRNA to the full
extent when compared to wt MERS-CoV probably due to the alternative pathways
that inhibit OAS dependent activation of RNAseL such as the orf4a dependent
sequestering of viral dsRNA intermediates. <o:p></o:p></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In addition to the localisation of orf4b, the presence of a second His residue within the PDE is important for the ability of orf4b to regulate the activity of RNaseL since substitution of the H182 (MERS-CoV) or H 186 (BtCoV SC2013) with R result in decreased ability of orf4b to inhibit RNaseL. </span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhoXuylF_a6GokR3wXcLuDigC1hmy3HPrT4jLHjaexeq8RlPyZCW-ss9b1bpjaEMVdestnY_eKDzyOWXJB9ehpeMHOeYBhhVI647ECeHm9j6MB0LqSsTcScNqaZLVtw_7PaX7E5QVJLx_-0/s1600/Blog+MERS+update.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhoXuylF_a6GokR3wXcLuDigC1hmy3HPrT4jLHjaexeq8RlPyZCW-ss9b1bpjaEMVdestnY_eKDzyOWXJB9ehpeMHOeYBhhVI647ECeHm9j6MB0LqSsTcScNqaZLVtw_7PaX7E5QVJLx_-0/s640/Blog+MERS+update.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: N-terminal NLS in orf4b is required for nuclear localisation of MERS-Cov<br />
and BtCoV off 4b</td></tr>
</tbody></table>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgnl3hlqtmkVhTT7POVpVkJkewBwaxniqhZuV-QHvH2HlPJ9n0cVYLNyB2sRPyZpNf254jgyBf8n346NZ_mI3h5_Z_nUkmcr_UVTF3aM62lUYw7HKbpLQwSoDpifCKFLt_8vazQlo1gvZDJ/s1600/Blog+MERS+update.005.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgnl3hlqtmkVhTT7POVpVkJkewBwaxniqhZuV-QHvH2HlPJ9n0cVYLNyB2sRPyZpNf254jgyBf8n346NZ_mI3h5_Z_nUkmcr_UVTF3aM62lUYw7HKbpLQwSoDpifCKFLt_8vazQlo1gvZDJ/s640/Blog+MERS+update.005.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Cytoplasmic localisation and His at position of 182 or 186 of MERS-CoV and BtCoV orf4b<br />
are required for inhibition of RNaseL</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="line-height: 14.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; mso-bidi-font-family: Times;">The induction of
antiviral signaling by via OAS/RNase L dependent pathways has also been
demonstrated for West Nile Virus (WNV), Influenza A Virus (IAV) and Vaccinia
Virus (VACV). OAS3 knockout cells infected with WNV, IAV, VACV or treated with
Poly(I:C) exhibit only minimal 2’-5’ oligoadenylate synthase activity and
infected A549, hTERT-HME and HT1080 OAS3 knockout cells display higher viral
titres than the corresponding wt cells. Interestingly, probably because of
increased expression of IFN-λ1, trophoblasts of the human placenta express
higher levels of OAS-1,-2, and -3 compared to JEG-3 cells, suggesting that
increased OAS levels contribute to the resistance of trophoblasts to ZIKV
resistance as well. <o:p></o:p></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjXk4DD8ItEGPMzuS5UrGmIynOE_mOBbIaxoOj3F88VObOGVhyD9RDxJ9IhjjmKEfqrvIqO3hPSXfesERyqXsgbKsOcgpmUxsA3RVOwYJ1IL3pqyXoCaKrSv5RMQ9lazY35DMjXBwLLxQse/s1600/Blog+MERS+update.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjXk4DD8ItEGPMzuS5UrGmIynOE_mOBbIaxoOj3F88VObOGVhyD9RDxJ9IhjjmKEfqrvIqO3hPSXfesERyqXsgbKsOcgpmUxsA3RVOwYJ1IL3pqyXoCaKrSv5RMQ9lazY35DMjXBwLLxQse/s640/Blog+MERS+update.006.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: orf4b degrades 2',5' OAS and prevents activation of RNaseL</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="line-height: 14.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="line-height: 14.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">More recently, the
viral M protein of both SARS-CoV and MERS-CoV but not HCoV-HKU1 has been
demonstrated to form a complex with the TRAF3 adapter protein, thus inhibiting
the formation of the TRAF3-TANK-TBK1/ IKK-ε complex via the N terminal domain
of the viral M protein. Consequently, the expression of MERS-CoV or SARS-CoV
inhibits RLR signaling induced by Sendai Virus or Poly (I:C) and further
analysis using RIG-1 and NF-κB reporter plasmids showed that the expression of
MERS-COV M preferentially inhibits RIG-1 mediated activation of IRF-3, thus
preventing the induction of IFN-β. Similar to SARS-CoV M, the interaction
between TRAF3 and MERS-CoV M is mediated by the N-terminal transmembrane domain
1 whereas the two other transmembrane domains as well as the C-terminal domain
are dispensable. Both the SARS-CoV and MERS-CoV derived M and ORF 4b protein
therefore inhibit antiviral RIG-1 by targeting the formation of the
TRAF3-TANK-TBK1/ IKK-ε complex, thus inhibiting IRF-3 dependent signaling. From
an experimental standpoint it would be interesting if a recombinant HCoV-HKU1
expressing MERS-CoV or SARS-CoV derived M exhibits increased viral titres
following infection of primary human cells compared to wt virus. Also, it
remains to be seen if the expression of MERS-CoV in </span><i style="font-family: 'helvetica neue', arial, helvetica, sans-serif;"><span style="font-size: large;">Artibeus jamaicensis</span> </i><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">or in bat derived cell lines inhibits the
antiviral signaling in a similar way. So far, the infection of </span><span style="font-family: 'helvetica neue', arial, helvetica, sans-serif;"><span style="font-size: large;"><i>Artibeus jamaicensis </i>with</span></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> MERS-CoV has
been demonstrated to increase the expression of Mx-1, ISG56 and RANTES
moderately suggesting that MERS-CoV does inhibit antiviral signaling in bats,
thus explaining the absence of clinical signs in infected bats despite the
presence of low viral titres in the duodenum of bats. The individual role of
ORF4a, ORF4b, ORF5 and M has not been assessed in bat or camel derived cell
lines. Indeed, the importance of the genetic and functional diversity of
proteins involved in the induction of antiviral signaling pathways has recently
been highlighted in studies comparing RIG-1 from waterfowl and mammals in their
capacity to facilitate an immune response to Influenza A virus. In short, duck
derived RIG-1 had a weaker ability to induce IFN compared to goose derived
RIG-1 and both duck and goose derived RIG-1 are more effective than pigeon
RIG-1 in (chicken) DF-1 cells infected with Influenza A virus.</span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhcocKSfLPJUq0vINmTk9F8nP5usMUAXRBi06W3Z-OUBoccc3tGq4PyYizBZMJncs3QgSoaeeWVGVwmmwLPBuoNVFNM7h5cRo4KLEnv1Hw4cXmWhOKmpEIl99YviNQUCiP6zKiChC5UEK6O/s1600/Blog+MERS+update.007.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhcocKSfLPJUq0vINmTk9F8nP5usMUAXRBi06W3Z-OUBoccc3tGq4PyYizBZMJncs3QgSoaeeWVGVwmmwLPBuoNVFNM7h5cRo4KLEnv1Hw4cXmWhOKmpEIl99YviNQUCiP6zKiChC5UEK6O/s640/Blog+MERS+update.007.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: MERS-CoV M, orf4a and orf4b: points of action</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="line-height: 14.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">So far it has not been
shown if the expression of mutant orf4b in the context of Coronavirus infection
not only abrogates immune signaling and thus promotes viral replication solely
by inhibiting apoptosis but also abrogates the induction of RNaseL induced
autophagy and degradation of viral replication centers. If so, the number of
viral RC should be increased in cells expressing mutant orf4b and/or mouse
embryonic fibroblasts derived from RNaseL -/- mice.</span></div>
<span style="float: left; padding: 5px;">
<span style="float: left; padding: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_gray.png" style="border: 0;" /></a></span>
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<w:LsdException Locked="false" Priority="9" SemiHidden="true"
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<w:LsdException Locked="false" Priority="9" SemiHidden="true"
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<w:LsdException Locked="false" Priority="9" SemiHidden="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" Priority="39" SemiHidden="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="35" SemiHidden="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="10" QFormat="true" Name="Title"/>
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="1" SemiHidden="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="22" QFormat="true" Name="Strong"/>
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" SemiHidden="true" UnhideWhenUsed="true"
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<w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 6"/>
<w:LsdException Locked="false" Priority="61" Name="Light List Accent 6"/>
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<w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 6"/>
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<w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 6"/>
<w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 6"/>
<w:LsdException Locked="false" Priority="19" QFormat="true"
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<w:LsdException Locked="false" Priority="21" QFormat="true"
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<w:LsdException Locked="false" Priority="31" QFormat="true"
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<w:LsdException Locked="false" Priority="32" QFormat="true"
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<w:LsdException Locked="false" Priority="33" QFormat="true" Name="Book Title"/>
<w:LsdException Locked="false" Priority="37" SemiHidden="true"
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padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span><br />
<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></u>
<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></u>
<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></u>
<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></u>
<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></u>
<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></u>
<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Further reading</span></u><br />
<div style="text-align: justify;">
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F25810418&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Middle+East+respiratory+syndrome+coronavirus%3A+another+zoonotic+betacoronavirus+causing+SARS-like+disease.&rft.issn=0893-8512&rft.date=2015&rft.volume=28&rft.issue=2&rft.spage=465&rft.epage=522&rft.artnum=&rft.au=Chan+JF&rft.au=Lau+SK&rft.au=To+KK&rft.au=Cheng+VC&rft.au=Woo+PC&rft.au=Yuen+KY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F25810418&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Middle+East+respiratory+syndrome+coronavirus%3A+another+zoonotic+betacoronavirus+causing+SARS-like+disease.&rft.issn=0893-8512&rft.date=2015&rft.volume=28&rft.issue=2&rft.spage=465&rft.epage=522&rft.artnum=&rft.au=Chan+JF&rft.au=Lau+SK&rft.au=To+KK&rft.au=Cheng+VC&rft.au=Woo+PC&rft.au=Yuen+KY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26572912&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Evidence+for+zoonotic+origins+of+Middle+East+respiratory+syndrome+coronavirus.&rft.issn=0022-1317&rft.date=2016&rft.volume=97&rft.issue=2&rft.spage=274&rft.epage=80&rft.artnum=&rft.au=Han+HJ&rft.au=Yu+H&rft.au=Yu+XJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26631542&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Middle+East+respiratory+syndrome+coronavirus+ORF4b+protein+inhibits+type+I+interferon+production+through+both+cytoplasmic+and+nuclear+targets.&rft.issn=&rft.date=2015&rft.volume=5&rft.issue=&rft.spage=17554&rft.epage=&rft.artnum=&rft.au=Yang+Y&rft.au=Ye+F&rft.au=Zhu+N&rft.au=Wang+W&rft.au=Deng+Y&rft.au=Zhao+Z&rft.au=Tan+W&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMolecular+Biology">Yang Y, Ye F, Zhu N, Wang W, Deng Y, Zhao Z, & Tan W (2015). Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets. <span style="font-style: italic;">Scientific reports, 5</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26631542" rev="review">26631542</a></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+biological+chemistry&rft_id=info%3Apmid%2F19380580&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Severe+acute+respiratory+syndrome+coronavirus+M+protein+inhibits+type+I+interferon+production+by+impeding+the+formation+of+TRAF3.TANK.TBK1%2FIKKepsilon+complex.&rft.issn=0021-9258&rft.date=2009&rft.volume=284&rft.issue=24&rft.spage=16202&rft.epage=9&rft.artnum=&rft.au=Siu+KL&rft.au=Kok+KH&rft.au=Ng+MH&rft.au=Poon+VK&rft.au=Yuen+KY&rft.au=Zheng+BJ&rft.au=Jin+DY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Siu KL, Kok KH, Ng MH, Poon VK, Yuen KY, Zheng BJ, & Jin DY (2009). Severe acute respiratory syndrome coronavirus M protein inhibits type I interferon production by impeding the formation of TRAF3.TANK.TBK1/IKKepsilon complex. <span style="font-style: italic;">The Journal of biological chemistry, 284</span> (24), 16202-9 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/19380580" rev="review">19380580</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Virology+Journal&rft_id=info%3Adoi%2F10.1186%2Fs12985-014-0209-9&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+SARS+coronavirus+papain+like+protease+can+inhibit+IRF3+at+a+post+activation+step+that+requires+deubiquitination+activity&rft.issn=1743-422X&rft.date=2014&rft.volume=11&rft.issue=1&rft.spage=&rft.epage=&rft.artnum=http%3A%2F%2Fwww.virologyj.com%2Fcontent%2F11%2F1%2F209&rft.au=Matthews%2C+K.&rft.au=Sch%C3%A4fer%2C+A.&rft.au=Pham%2C+A.&rft.au=Frieman%2C+M.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Matthews, K., Schäfer, A., Pham, A., & Frieman, M. (2014). The SARS coronavirus papain like protease can inhibit IRF3 at a post activation step that requires deubiquitination activity <span style="font-style: italic;">Virology Journal, 11</span> (1) DOI: <a href="http://dx.doi.org/10.1186/s12985-014-0209-9" rev="review">10.1186/s12985-014-0209-9</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Virology&rft_id=info%3Adoi%2F10.1128%2FJVI.03649-13&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Middle+East+Respiratory+Syndrome+Coronavirus+4a+Protein+Is+a+Double-Stranded+RNA-Binding+Protein+That+Suppresses+PACT-Induced+Activation+of+RIG-I+and+MDA5+in+the+Innate+Antiviral+Response&rft.issn=0022-538X&rft.date=2014&rft.volume=88&rft.issue=9&rft.spage=4866&rft.epage=4876&rft.artnum=http%3A%2F%2Fjvi.asm.org%2Fcgi%2Fdoi%2F10.1128%2FJVI.03649-13&rft.au=Siu%2C+K.&rft.au=Yeung%2C+M.&rft.au=Kok%2C+K.&rft.au=Yuen%2C+K.&rft.au=Kew%2C+C.&rft.au=Lui%2C+P.&rft.au=Chan%2C+C.&rft.au=Tse%2C+H.&rft.au=Woo%2C+P.&rft.au=Yuen%2C+K.&rft.au=Jin%2C+D.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Siu, K., Yeung, M., Kok, K., Yuen, K., Kew, C., Lui, P., Chan, C., Tse, H., Woo, P., Yuen, K., & Jin, D. (2014). Middle East Respiratory Syndrome Coronavirus 4a Protein Is a Double-Stranded RNA-Binding Protein That Suppresses PACT-Induced Activation of RIG-I and MDA5 in the Innate Antiviral Response <span style="font-style: italic;">Journal of Virology, 88</span> (9), 4866-4876 DOI: <a href="http://dx.doi.org/10.1128/JVI.03649-13" rev="review">10.1128/JVI.03649-13</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Emerging+microbes+%26+infections&rft_id=info%3Apmid%2F27094905&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Middle+East+respiratory+syndrome+coronavirus+M+protein+suppresses+type+I+interferon+expression+through+the+inhibition+of+TBK1-dependent+phosphorylation+of+IRF3.&rft.issn=&rft.date=2016&rft.volume=5&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Lui+PY&rft.au=Wong+LY&rft.au=Fung+CL&rft.au=Siu+KL&rft.au=Yeung+ML&rft.au=Yuen+KS&rft.au=Chan+CP&rft.au=Woo+PC&rft.au=Yuen+KY&rft.au=Jin+DY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Lui PY, Wong LY, Fung CL, Siu KL, Yeung ML, Yuen KS, Chan CP, Woo PC, Yuen KY, & Jin DY (2016). Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3. <span style="font-style: italic;">Emerging microbes & infections, 5</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27094905" rev="review">27094905</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F24443473&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+ORF4b-encoded+accessory+proteins+of+Middle+East+respiratory+syndrome+coronavirus+and+two+related+bat+coronaviruses+localize+to+the+nucleus+and+inhibit+innate+immune+signalling.&rft.issn=0022-1317&rft.date=2014&rft.volume=95&rft.issue=Pt+4&rft.spage=874&rft.epage=82&rft.artnum=&rft.au=Matthews+KL&rft.au=Coleman+CM&rft.au=van+der+Meer+Y&rft.au=Snijder+EJ&rft.au=Frieman+MB&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMicrobiology">Matthews KL, Coleman CM, van der Meer Y, Snijder EJ, & Frieman MB (2014). The ORF4b-encoded accessory proteins of Middle East respiratory syndrome coronavirus and two related bat coronaviruses localize to the nucleus and inhibit innate immune signalling. <span style="font-style: italic;">The Journal of general virology, 95</span> (Pt 4), 874-82 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24443473" rev="review">24443473</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=mBio&rft_id=info%3Apmid%2F27025250&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Middle+East+Respiratory+Syndrome+Coronavirus+NS4b+Protein+Inhibits+Host+RNase+L+Activation.&rft.issn=&rft.date=2016&rft.volume=7&rft.issue=2&rft.spage=&rft.epage=&rft.artnum=&rft.au=Thornbrough+JM&rft.au=Jha+BK&rft.au=Yount+B&rft.au=Goldstein+SA&rft.au=Li+Y&rft.au=Elliott+R&rft.au=Sims+AC&rft.au=Baric+RS&rft.au=Silverman+RH&rft.au=Weiss+SR&rfe_dat=bpr3.included=1;bpr3.tags=">Thornbrough JM, Jha BK, Yount B, Goldstein SA, Li Y, Elliott R, Sims AC, Baric RS, Silverman RH, & Weiss SR (2016). Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation. <span style="font-style: italic;">mBio, 7</span> (2) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27025250" rev="review">27025250</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> <span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Viruses&rft_id=info%3Apmid%2F26205406&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Pigeon+RIG-I+Function+in+Innate+Immunity+against+H9N2+IAV+and+IBDV.&rft.issn=&rft.date=2015&rft.volume=7&rft.issue=7&rft.spage=4131&rft.epage=51&rft.artnum=&rft.au=Xu+W&rft.au=Shao+Q&rft.au=Zang+Y&rft.au=Guo+Q&rft.au=Zhang+Y&rft.au=Li+Z&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Xu W, Shao Q, Zang Y, Guo Q, Zhang Y, & Li Z (2015). Pigeon RIG-I Function in Innate Immunity against H9N2 IAV and IBDV. <span style="font-style: italic;">Viruses, 7</span> (7), 4131-51 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26205406" rev="review">26205406</a></span></span>thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-2080318443413859172016-04-13T18:35:00.002-04:002016-04-14T12:10:51.585-04:00Zika Virus and induction of apoptosis: combination of IFN-β and downregulation of gene expression?<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">As
described in a<a href="http://virologytidbits.blogspot.com/2016/04/zikv-pathogenesis-development-of-animal.html" target="_blank"> </a><a href="http://virologytidbits.blogspot.com/2016/04/zikv-pathogenesis-development-of-animal.html" target="_blank">previous post</a>, Zika virus (ZIKV) infection of primary human skin
fibroblasts induces the upregulation of TLR3 mRNA as well as inducing the
expression of MDA-5 and RIG-1, components of the antiviral response induced not
only ZIKV but by RNA viruses in general. As a result of the activation of RIG-1
and MDA-5, the expression of both Interferon-α (IFN-α) and Interferon-β (IFN-β)
is increased. In mouse models such as A129, AG129 or Ifnar1 -/- mice that are
deficient for either the receptor for IFN-α or both for IFN-α and IFN-β, higher
viral loads are established in a number of tissues compared to wt mice,
suggesting that the induction of IFN-α and IFN-β by ZIKV limits viral
replication. Interestingly, in human neural progenitor cells (hNPC) infected
with ZIKV the expression of IFNAR-1 (the human equivalent of Ifnar-1) is
downregulated whereas the expression of the IFN-γ receptor (IFNGR-1) is
upregulated. The induction of the type I IFN response can however also
contribute to the severity of viral infections as shown for SARS-CoV in mice.
In infected mice, the delay of the induction of type I IFN by SARS-CoV
contributes to the accumulation of pathogenic inflammatory monocyte derived
macrophages, resulting in elevated levels cytokines and chemokines as well as
vascular leakage and the impairment of virus specific T cell responses, thus
contributing to decreased survival of infected mice compared to Ifnar-1 -/-
mice. Furthermore, blocking the IFNAR-1 receptor and deleting IFN-β in mice
promotes the clearance of lymphocytic choriomengitis virus (LCMV) in mice
whereas the activation of IFN-α inhibits early dissemination of LCMV. In
contrast to SARS-CoV and LCMV however, Ifnar1 -/-, A129 and AG129 mice show a
decreased survival rate, indicating that IFN-α is necessary for viral clearance
and survival of infected mice.<o:p></o:p></span></span></div>
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<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The
infection of hNPC with ZIKV MR766 induces the downregulation of a number of
genes promoting cell survival including those encoding for anti-apoptotic
proteins, cell cycle regulators, factors involved in the DNA damage response
pathway and autophagy as well inducing apoptosis that is preceded by an arrest
in G2/M phase of the cell cycle. <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In
addition, human neurospheres and brain organoids infected with ZIKV MR766
exhibit extensive caspase-3 dependent cell death as early as 3 days p.i. which
is in agreement with previous results that showed that 56 hrs p.i. the
expression of Caspase-3 is upregulated, suggesting that in human neuronal cells
ZIKV induces Caspase-3 dependent apoptosis. None of these experiments however
determined the contributing factors, i.e. the pathway of apoptosis induction.<o:p></o:p></span></span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh9A4N2e4QRDIyXqneUAR2_XbXyoaBjgiD10tkqve22LN6m8SrRDEZLATnTc58fFDZ30c1gUj8IBzksUl7Le80rq4htusDR9Ki9oXSkFswRAta22_DvqvY51tXBkvsZAf_40UmRer4d0TUx/s1600/Untitled+2.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh9A4N2e4QRDIyXqneUAR2_XbXyoaBjgiD10tkqve22LN6m8SrRDEZLATnTc58fFDZ30c1gUj8IBzksUl7Le80rq4htusDR9Ki9oXSkFswRAta22_DvqvY51tXBkvsZAf_40UmRer4d0TUx/s640/Untitled+2.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Changes of gene expression in hNPC infected with ZIKV compared to Mock infected<br />
cells; RECQL4, IFNAR-1, IRF-7, IFIT-2</td></tr>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The
infection of human lung epithelial A549 cells with ZIKV PF/25013/18 results in
effective viral replication as measured by immunofluorescence for the viral E
protein and dsRNA, flow cytometry for E protein positive cells, and determination
of viral titres that showed maximum titres within 48 hrs p.i. concomitant with
the induction of PARP cleavage and decreased cell viability. RT-PCR analysis of
ZIKV infected cells revealed that ZIKV infection induces a 200-fold increase of
both IFIT-1 (ISG56) and IFIT-2 (ISG54), both of which are regulated by IRF-3
and IRF-7 as well as STAT-1/-2 (in addition to A549 cells, ZIKV also
upregulates IFIT-2 and IRF-7 expression in hNPC). Since IFIT-2 induces the
depolarization of mitochondria and thus contributes to the induction of
Caspase-3 and -9 dependent apoptosis, it might be possible that the formation of
the complex consisting of IFIT-1 and IFIT-2 is induced by ZIKV and induces
apoptosis in a Bak and Bax dependent manner. Unfortunately, the current data do
not contain experiments using either Bak -/- Bax -/- cells nor cells that are
deficient for either IFIT-1/-2 or cells treated with siRNA targeting Bak, Bax,
IFIT-1 or IFIT-2. Downstream of IFIT-1 and IFIT2, the infection of A549 cells
with ZIKV triggers the production of mitochondrial reactive oxygen species
(ROS) as detected by MitoSOX without increasing cytoplasmic ROS levels similar
to cells infected with DENV by increasing the expression of mitochondrial SOD2
although in the case of DENV infected cells cytoplasmic ROS levels are
increased as the result of DENV induced activation of the ER stress response.
If the downregulation of RecQL4 expression in ZIKV infected cells contributes
to the activation of SOD2 is a contributing factor is not known, but possible. Alternatively,
ZIKV proteins localizing to the ER might induce the ER stress response and thus
induce the expression of mitochondrial ROS independent of IFIT-1/-2.</span></div>
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<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Also
it remains to be seen if the expression of IFN-β in ZIKV infected cells can be
induced via the relocalisation of STING to perinuclear punctae. <o:p></o:p></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg43dHuHI7ecwKJT57BCDDZoym1MVd9caZDNqWKM6udwtF_6LhbeB-PcoOxbTfJu1uFsuX-BzwCPYVGuMFSofFRaGZOMjuiAiGC2KRwxfcbMUGjt13BOs-kqnVwrfr7_JGiKaz_V8COyckP/s1600/Untitled+2.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg43dHuHI7ecwKJT57BCDDZoym1MVd9caZDNqWKM6udwtF_6LhbeB-PcoOxbTfJu1uFsuX-BzwCPYVGuMFSofFRaGZOMjuiAiGC2KRwxfcbMUGjt13BOs-kqnVwrfr7_JGiKaz_V8COyckP/s640/Untitled+2.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Induction of STING signalling by delocalisation of STING to perinuclear punctae</td></tr>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The
infection of primary human skin fibroblasts with ZIKV induces the expression of
pro-inflammatory cytokines which can also be detected in patients infected with
ZIKV. Accordingly, the infection of A549 cells induces the expression of IL-1β,
IL-6 and MCP-1 at 24-48 hrs p.i.. IFN-β expression and secretion can be
detected at early times post infection (12 hrs p.i., increasing between 18-24
hrs p.i.), suggesting that the induction of IFN-β increases the expression of
both IFIT-1 and IFIT-2 contributing to the induction of apoptosis.
Interestingly, pretreatment of A549 cells with IFN-β not only reduces viral
titres but also reduces caspase-3 activity suggesting that other factors than
the IFIT-1/IFIT-2 complex trigger apoptosis. Since IFN-β not only triggers an
antiviral response and apoptosis but also autophagy, pretreatment of A549 cells
might induce the formation of autophagosomes that not only promotes the
degradation of viral particles upon entry but also promotes the degradation of
viral RNA in a process called RNautophagy. Further studies are however needed
to verify and explore this pathway. Since the infection of mouse embryonic
fibroblasts (MEF) with West Nile Virus (WNV) or Japanese Encephalitis Virus
(JEV) activates the inflammasome, pretreatment of A549 cells might prime cells
to MEFV dependent inactivation of the inflammasome and thus apoptosis following
inflammasome activation by ZIKV. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEie2HDDOmjrPeNENTRHXFmlGpwESDjWp4NxrAUkxMhNVN8ZSc2-BtOM_6czVixxmdoCNCFW3tx3WF9hZF5Ni6RJtnRmBf12uGKIeP4gEQPINksKykKd9sGwlU3UEF6fZSAGN3-EVT42CNec/s1600/Untitled+2.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEie2HDDOmjrPeNENTRHXFmlGpwESDjWp4NxrAUkxMhNVN8ZSc2-BtOM_6czVixxmdoCNCFW3tx3WF9hZF5Ni6RJtnRmBf12uGKIeP4gEQPINksKykKd9sGwlU3UEF6fZSAGN3-EVT42CNec/s640/Untitled+2.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Induction of SOD2: dependent on downregulation of RECQL4 and/or induction of <br />
ER stress response </td></tr>
</tbody></table>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In
conclusion, the infection of A549 cells with ZIKV results in productive
infection and triggers an antiviral response that includes the expression of
chemokines, IFN-β, and IFIT-1 as well as IFIT-2, similar to observations from
ZIKV patients or ZIKV infected hNPC. Similar to hNPC, neurospheres, and brain
organoids, ZIKV triggers caspase dependent apoptosis probably in a IFIT-1/-2
independent manner, although further experiments are warranted. Pretreatment
and treatment up to 2 hrs p.i. of A549 cells with IFN-β results in decreased
viral titres and decreased caspase-3 activation suggesting that IFN-β has a
pro-survival rather than a pro-apoptotic role in ZIKV infection, a notion that
is supported by observations from existing mouse models. The increase of
mitochondrial ROS by ZIKV might induce DNA damage that due to the potential
inhibition of the DNA damage response by ZIKV might induce cell cycle arrest
and subsequent apoptosis as well MAVS/RIG1 mediated induction of IFN expression
and/or MAPK/NFκ-B mediated increase of chemokines.</span></div>
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<a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_gray.png" style="border: 0;" /></a></div>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+infection&rft_id=info%3Apmid%2F26940504&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+fever+and+congenital+Zika+syndrome%3A+An+unexpected+emerging+arboviral+disease.&rft.issn=0163-4453&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Chan+JF&rft.au=Choi+GK&rft.au=Yip+CC&rft.au=Cheng+VC&rft.au=Yuen+KY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+infection&rft_id=info%3Apmid%2F26940504&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+fever+and+congenital+Zika+syndrome%3A+An+unexpected+emerging+arboviral+disease.&rft.issn=0163-4453&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Chan+JF&rft.au=Choi+GK&rft.au=Yip+CC&rft.au=Cheng+VC&rft.au=Yuen+KY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span><span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+infection&rft_id=info%3Apmid%2F26940504&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+fever+and+congenital+Zika+syndrome%3A+An+unexpected+emerging+arboviral+disease.&rft.issn=0163-4453&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Chan+JF&rft.au=Choi+GK&rft.au=Yip+CC&rft.au=Cheng+VC&rft.au=Yuen+KY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u style="font-family: 'helvetica neue', arial, helvetica, sans-serif; text-align: justify;">Further reading</u></span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Chan JF, Choi GK, Yip CC, Cheng VC, & Yuen KY (2016). Zika fever and congenital Zika syndrome: An unexpected emerging arboviral disease. </span><span style="font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-style: italic;">The Journal of infection</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">PMID: </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/26940504" rev="review" style="font-family: 'helvetica neue', arial, helvetica, sans-serif;"><span style="font-size: large;">26940504</span></a></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F26867177&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dysregulated+Type+I+Interferon+and+Inflammatory+Monocyte-Macrophage+Responses+Cause+Lethal+Pneumonia+in+SARS-CoV-Infected+Mice.&rft.issn=1931-3128&rft.date=2016&rft.volume=19&rft.issue=2&rft.spage=181&rft.epage=93&rft.artnum=&rft.au=Channappanavar+R&rft.au=Fehr+AR&rft.au=Vijay+R&rft.au=Mack+M&rft.au=Zhao+J&rft.au=Meyerholz+DK&rft.au=Perlman+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
<div style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F26867177&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dysregulated+Type+I+Interferon+and+Inflammatory+Monocyte-Macrophage+Responses+Cause+Lethal+Pneumonia+in+SARS-CoV-Infected+Mice.&rft.issn=1931-3128&rft.date=2016&rft.volume=19&rft.issue=2&rft.spage=181&rft.epage=93&rft.artnum=&rft.au=Channappanavar+R&rft.au=Fehr+AR&rft.au=Vijay+R&rft.au=Mack+M&rft.au=Zhao+J&rft.au=Meyerholz+DK&rft.au=Perlman+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, & Perlman S (2016). Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. <span style="font-style: italic;">Cell host & microbe, 19</span> (2), 181-93 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26867177" rev="review">26867177</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+host+%26+microbe&rft_id=info%3Apmid%2F25974304&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Blockade+of+interferon+Beta%2C+but+not+interferon+alpha%2C+signaling+controls+persistent+viral+infection.&rft.issn=1931-3128&rft.date=2015&rft.volume=17&rft.issue=5&rft.spage=653&rft.epage=61&rft.artnum=&rft.au=Ng+CT&rft.au=Sullivan+BM&rft.au=Teijaro+JR&rft.au=Lee+AM&rft.au=Welch+M&rft.au=Rice+S&rft.au=Sheehan+KC&rft.au=Schreiber+RD&rft.au=Oldstone+MB&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Ng CT, Sullivan BM, Teijaro JR, Lee AM, Welch M, Rice S, Sheehan KC, Schreiber RD, & Oldstone MB (2015). Blockade of interferon Beta, but not interferon alpha, signaling controls persistent viral infection. <span style="font-style: italic;">Cell host & microbe, 17</span> (5), 653-61 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25974304" rev="review">25974304</a></span> </span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, Yao B, Shin J, Zhang F, Lee EM, Christian KM, Didier RA, Jin P, Song H, & Ming GL (2016). Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. <span style="font-style: italic;">Cell stem cell</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26952870" rev="review">26952870</a></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+American+journal+of+tropical+medicine+and+hygiene&rft_id=info%3Apmid%2F27022155&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Characterization+of+a+Novel+Murine+Model+to+Study+Zika+Virus.&rft.issn=0002-9637&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Rossi+SL&rft.au=Tesh+RB&rft.au=Azar+SR&rft.au=Muruato+AE&rft.au=Hanley+KA&rft.au=Auguste+AJ&rft.au=Langsjoen+RM&rft.au=Paessler+S&rft.au=Vasilakis+N&rft.au=Weaver+SC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Rossi SL, Tesh RB, Azar SR, Muruato AE, Hanley KA, Auguste AJ, Langsjoen RM, Paessler S, Vasilakis N, & Weaver SC (2016). Characterization of a Novel Murine Model to Study Zika Virus. <span style="font-style: italic;">The American journal of tropical medicine and hygiene</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27022155" rev="review">27022155</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Oncotarget&rft_id=info%3Apmid%2F26958937&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Oroxylin+a+modulates+mitochondrial+function+and+apoptosis+in+human+colon+cancer+cells+by+inducing+mitochondrial+translocation+of+wild-type+p53.&rft.issn=&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Qiao+C&rft.au=Lu+N&rft.au=Zhou+Y&rft.au=Ni+T&rft.au=Dai+Y&rft.au=Li+Z&rft.au=Guo+Q&rft.au=Wei+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Qiao C, Lu N, Zhou Y, Ni T, Dai Y, Li Z, Guo Q, & Wei L (2016). Oroxylin a modulates mitochondrial function and apoptosis in human colon cancer cells by inducing mitochondrial translocation of wild-type p53. <span style="font-style: italic;">Oncotarget</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26958937" rev="review">26958937</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Scientific+reports&rft_id=info%3Apmid%2F26906558&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Pyruvate+Carboxylase+Activates+the+RIG-I-like+Receptor-Mediated+Antiviral+Immune+Response+by+Targeting+the+MAVS+signalosome.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=&rft.spage=22002&rft.epage=&rft.artnum=&rft.au=Cao+Z&rft.au=Zhou+Y&rft.au=Zhu+S&rft.au=Feng+J&rft.au=Chen+X&rft.au=Liu+S&rft.au=Peng+N&rft.au=Yang+X&rft.au=Xu+G&rft.au=Zhu+Y&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Cao Z, Zhou Y, Zhu S, Feng J, Chen X, Liu S, Peng N, Yang X, Xu G, & Zhu Y (2016). Pyruvate Carboxylase Activates the RIG-I-like Receptor-Mediated Antiviral Immune Response by Targeting the MAVS signalosome. <span style="font-style: italic;">Scientific reports, 6</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26906558" rev="review">26906558</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">West, A., Shadel, G., & Ghosh, S. (2011). Mitochondria in innate immune responses <span style="font-style: italic;">Nature Reviews Immunology, 11</span> (6), 389-402 DOI: <a href="http://dx.doi.org/10.1038/nri2975" rev="review">10.1038/nri2975</a></span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Autophagy&rft_id=info%3Apmid%2F23221969&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=IFNB1%2Finterferon-%CE%B2-induced+autophagy+in+MCF-7+breast+cancer+cells+counteracts+its+proapoptotic+function.&rft.issn=1554-8627&rft.date=2013&rft.volume=9&rft.issue=3&rft.spage=287&rft.epage=302&rft.artnum=&rft.au=Ambj%C3%B8rn+M&rft.au=Ejlerskov+P&rft.au=Liu+Y&rft.au=Lees+M&rft.au=J%C3%A4%C3%A4ttel%C3%A4+M&rft.au=Issazadeh-Navikas+S&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Ambjørn M, Ejlerskov P, Liu Y, Lees M, Jäättelä M, & Issazadeh-Navikas S (2013). IFNB1/interferon-β-induced autophagy in MCF-7 breast cancer cells counteracts its proapoptotic function. <span style="font-style: italic;">Autophagy, 9</span> (3), 287-302 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/23221969" rev="review">23221969</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Autophagy&rft_id=info%3Apmid%2F27046251&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Lysosomal+putative+RNA+transporter+SIDT2+mediates+direct+uptake+of+RNA+by+lysosomes.&rft.issn=1554-8627&rft.date=2016&rft.volume=12&rft.issue=3&rft.spage=565&rft.epage=78&rft.artnum=&rft.au=Aizawa+S&rft.au=Fujiwara+Y&rft.au=Contu+VR&rft.au=Hase+K&rft.au=Takahashi+M&rft.au=Kikuchi+H&rft.au=Kabuta+C&rft.au=Wada+K&rft.au=Kabuta+T&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Aizawa S, Fujiwara Y, Contu VR, Hase K, Takahashi M, Kikuchi H, Kabuta C, Wada K, & Kabuta T (2016). Lysosomal putative RNA transporter SIDT2 mediates direct uptake of RNA by lysosomes. <span style="font-style: italic;">Autophagy, 12</span> (3), 565-78 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27046251" rev="review">27046251</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Autophagy&rft_id=info%3Apmid%2F26983397&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=TRIM-Directed+Selective+Autophagy+Regulates+Immune+Activation.&rft.issn=1554-8627&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Kimura+T&rft.au=Jain+A&rft.au=Choi+SW&rft.au=Mandell+MA&rft.au=Johansen+T&rft.au=Deretic+V&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Kimura T, Jain A, Choi SW, Mandell MA, Johansen T, & Deretic V (2016). TRIM-Directed Selective Autophagy Regulates Immune Activation. <span style="font-style: italic;">Autophagy</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26983397" rev="review">26983397</a></span></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+Pathogens&rft_id=info%3Adoi%2F10.1371%2Fjournal.ppat.1003541&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Innate+Immune+Sensing+of+Flaviviruses&rft.issn=1553-7374&rft.date=2013&rft.volume=9&rft.issue=9&rft.spage=0&rft.epage=&rft.artnum=http%3A%2F%2Fdx.plos.org%2F10.1371%2Fjournal.ppat.1003541&rft.au=Suthar%2C+M.&rft.au=Aguirre%2C+S.&rft.au=Fernandez-Sesma%2C+A.&rfe_dat=bpr3.included=1;bpr3.tags=">Suthar, M., Aguirre, S., & Fernandez-Sesma, A. (2013). Innate Immune Sensing of Flaviviruses <span style="font-style: italic;">PLoS Pathogens, 9</span> (9) DOI: <a href="http://dx.doi.org/10.1371/journal.ppat.1003541" rev="review">10.1371/journal.ppat.1003541</a></span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+cell+biology&rft_id=info%3Apmid%2F23624402&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ER-stress-induced+transcriptional+regulation+increases+protein+synthesis+leading+to+cell%C2%A0death.&rft.issn=1465-7392&rft.date=2013&rft.volume=15&rft.issue=5&rft.spage=481&rft.epage=90&rft.artnum=&rft.au=Han+J&rft.au=Back+SH&rft.au=Hur+J&rft.au=Lin+YH&rft.au=Gildersleeve+R&rft.au=Shan+J&rft.au=Yuan+CL&rft.au=Krokowski+D&rft.au=Wang+S&rft.au=Hatzoglou+M&rft.au=Kilberg+MS&rft.au=Sartor+MA&rft.au=Kaufman+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology">Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, & Kaufman RJ (2013). ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. <span style="font-style: italic;">Nature cell biology, 15</span> (5), 481-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/23624402" rev="review">23624402</a></span>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-86542473309226505552016-04-11T16:19:00.002-04:002016-04-13T15:22:14.698-04:00ZIKV pathogenesis: development of animal models<span style="float: left; padding: 5px;"><br /></span><span style="float: left; padding: 5px;"><br /></span>
<span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"></span><br />
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<span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
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<span class="Z3988" style="font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Zika
Virus (ZIKV) is a emerging positive strand RNA virus that belongs to the genus
of <i style="mso-bidi-font-style: normal;">Flaviviridae</i>. Human infections are
mostly asymptomatic although a causative link to microcephaly and Guillan-Barre
Syndrome (GBS) have been proposed. <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">So
far however no reliable animal model to study ZIKV associated disease has been
identified but in order to test a potential vaccine and order to gain a better
understanding of ZIKV pathogenesis animal models are being developed. Similar to
DENV, these models may involve immunocompetent and humanized mice as well
nonhuman primates. <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Here
recent advances to establish a mouse model are presented.<span style="mso-spacerun: yes;">
</span><o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="mso-spacerun: yes;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></span><b style="mso-bidi-font-weight: normal;"><span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">ZIKV in mice</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></b></span></div>
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<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In
the original mouse model, ZIKV was first isolated from Swiss albino mice
intracerebrallly injected with the original ZIKV 766 strain that was isolated
from the sentinel rhesus monkey as well as virus suspensions obtained from
infected <i style="mso-bidi-font-style: normal;">Aedes Africanus</i> mosquitoes.
Following the 16 passages of ZIKV strain 766 in mice, 100% mortality can be
observed and subsequent infections of mice with (mouse adapted) ZIKV 766 lead
to a mean survival time of 10.6 days with an incubation period of 6 days.<o:p></o:p></span></span></div>
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<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Both
the infection of mice with ZIKV 758 isolated from rhesus monkeys and the E/1
strain isolated from infected<i style="mso-bidi-font-style: normal;"> A.
Africanus</i> resulted in 100% mortality at passage 16 and 15 indicating that
the intracerebral injection of ZIKV suspensions in and subsequent adaption of
rhesus and mosquitoe derived ZIKV to mice results in sickness (indicated by
roughness of the fur and inactivity), paralysis (motor weakness and paralysis
of limbs) and death within 24 to 48 hrs p.i. . <o:p></o:p></span></span><br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhjg_jT5uUcmR6q1G4fNph4odktk555AdaoX4X39jQoDZI7TgcRSvQ8L6EWNGrXkVZbUopKTxwMdyEs6uS0YJM1wYHkhyphenhyphenkkzW2lJGrFu4T1RjDYuGFWawtqMNfVX7P958OamMBnCc6-q3Bs/s1600/ZIKV+pathogenesis+blog.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhjg_jT5uUcmR6q1G4fNph4odktk555AdaoX4X39jQoDZI7TgcRSvQ8L6EWNGrXkVZbUopKTxwMdyEs6uS0YJM1wYHkhyphenhyphenkkzW2lJGrFu4T1RjDYuGFWawtqMNfVX7P958OamMBnCc6-q3Bs/s640/ZIKV+pathogenesis+blog.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV in Swiss albino mice: number of healthy, sick and paralysed mice </td></tr>
</tbody></table>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjA1CEpIJXP2Fh944zPnJtDDjOJEvvyOHEQPHFNtMKPGAG0e7RzS__18XKX0wcrW58klfsJyFOHnJ2OY1bGxsxGI_2vMoyXElHReQUsu99E1eANtJbj2RBajkc8zIorlUkEpfu1J7REETXV/s1600/ZIKV+pathogenesis+blog.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjA1CEpIJXP2Fh944zPnJtDDjOJEvvyOHEQPHFNtMKPGAG0e7RzS__18XKX0wcrW58klfsJyFOHnJ2OY1bGxsxGI_2vMoyXElHReQUsu99E1eANtJbj2RBajkc8zIorlUkEpfu1J7REETXV/s640/ZIKV+pathogenesis+blog.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV in Swiss albino mice: number of dead mice</td></tr>
</tbody></table>
<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";">Subsequent
intracerebral (i.c.) infection of newborn and 5 week old mice with ZIKV MP1751
strain showed that ZIKV replicates in both neurons and astroglial cells as well
as extensive cell death in the hippocampus and cortex of infected mice,
suggesting that apoptosis or necrosis of brain cells might be the cause of
paralysis. Recently published data obtained from human cortical neuron
progenitor cells infected with ZIKV 766 indicate that infected neuronal cell
indeed undergo apoptosis probably by ZIKV induced downregulation of
anti-apoptotic genes, thus explaining the loss of neuronal cells in ZIKV (</span><span lang="EN-GB" style="font-family: "helvetica"; mso-ansi-language: EN-GB;">intercelebrally;
i.c.</span><span style="font-family: "helvetica";">) infected mice. The initial
experiments also revealed that mice infected intraperitoneally (i.p.) at 7 days
of age exhibited a higher LD<sub>50</sub> value than those 14 days or older at
time of infection although mice older than 6 weeks are slightly less
susceptible than younger mice to i.c. infection.</span></span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg_YJvH0JTXGdG0lbF5wWOceiCOp6JVQ4uEBZEEUDY98E3wL89XJ_NH4NiPN2YJ7lNoZcIDaZHS-IgACi6S_CVIJ2hJmUuwyHEuTBpOw60pQkBfEUDDmdhOH1QNI3tBaCaIFNwflZOW3Evu/s1600/ZIKV+pathogenesis+blog.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg_YJvH0JTXGdG0lbF5wWOceiCOp6JVQ4uEBZEEUDY98E3wL89XJ_NH4NiPN2YJ7lNoZcIDaZHS-IgACi6S_CVIJ2hJmUuwyHEuTBpOw60pQkBfEUDDmdhOH1QNI3tBaCaIFNwflZOW3Evu/s640/ZIKV+pathogenesis+blog.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: LD50 values are influenced by age of mice at time of infection</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";"><br /></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Interestingly, recent data
indicate that the infection of 7 days old mice intraperitoneally infected with
ZIKV Dakar 41519 reduces viability by 33% compared to mice infected
subcutaneously (s.c.), suggesting that the route of infection as well as the
age at time of infection indeed effects the survival rate. <o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif;">Initially,
ZIKV was not detected in any other organs following infection i.c., but in more
recent studies in A129 and AG129 mice infected either i.p. or intradermal
(i.d.) with ZIKV FSS13025 (Asian lineage) showed high viral titres in the
kidney, spleen, testes, and brain of infected mice suggesting that the route of
infection might not only determine the survival rate but also sites or viral
replication. Comparing these results with those obtained originally using Swiss
albino mice suggest that ZIKV infection in mice induces the antiviral
Interferon response since A129 mice are deficient for both Interferon-α and –β
(IFN-α /-β) whereas AG129 are deficient not only for IFN-α /-β but also for
</span><span style="font-family: "helvetica";">IFN-</span></span><span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">γ. The notion that ZIKV induces
the interferon response is supported by recently published studies in primary
skin fibroblasts and human placenta cells as well as in triple knockout mice.</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="mso-spacerun: yes;"> </span><b><i>ZIKV: induction
of the Interferon response <o:p></o:p></i></b></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Infection
of primary human skin fibroblasts with low passage ZIKV strain derived from a
viremic patient in Tahiti/French Polynesia, PF-25013-18, results in the
activation of the innate immune response namely the induction of Pattern
Recognition Receptors (PRRs) by the viral RNA. As indicated by analysing the
expression of genes using qRT-PCR, the expression of TLR3, RIG-1/DDX58 and
MDA5/IFIH1 as well as CXCL10, Interleukin-1β, AIM2 is upregulated whereas the
expression of others such as TLR7, TLR8, or TNF is downregulated as soon as 6
hrs p.i.. Activation of TLR3, RIG1 and MDA5 expression increases also the
expression of Interferon stimulated genes (ISG) including OAS2, ISG15 and MX1,
suggesting that ZIKV RNA activates PRRs dependent downstream signaling pathways
by binding to TLR3, MDA5 and RIG-1 which subsequently stimulate the expression
of ISG via upregulation of IRF7 expression. Since IRF7 is a transcription
factor for type I interferons, the infection of primary skin cells with ZIKV
induces an antiviral response that decreases viral titres. <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi69D01_CPQKBnbnlMt3Ze65P9ElZSOj1eOzhlLxjtZNmRrtyzXf3qFBZsfWzaIijMsnWhOvx6_93eFRvnkM7wv9_boAl8WRH7l-gTUsLjdWTB76-SpYGWWQGgU-7kSGutXoTKG1XcMbDcl/s1600/ZIKV+pathogenesis+blog.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi69D01_CPQKBnbnlMt3Ze65P9ElZSOj1eOzhlLxjtZNmRrtyzXf3qFBZsfWzaIijMsnWhOvx6_93eFRvnkM7wv9_boAl8WRH7l-gTUsLjdWTB76-SpYGWWQGgU-7kSGutXoTKG1XcMbDcl/s640/ZIKV+pathogenesis+blog.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Genes that are unregulated in PHT cells</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj2fNNPinmsik22NJrgTaBsrVoioiw0Viis8NdJbXYJJJKIp4HewZyt5JQ_rXsS9IiJImWxOXzCBb87UftBWIJvxOlLziTKhZPyNE8VqtZFgYcYUT2QheHs1GjVN-XYYcfuen4t-rtUgWgW/s1600/ZIKV+pathogenesis+blog.005.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj2fNNPinmsik22NJrgTaBsrVoioiw0Viis8NdJbXYJJJKIp4HewZyt5JQ_rXsS9IiJImWxOXzCBb87UftBWIJvxOlLziTKhZPyNE8VqtZFgYcYUT2QheHs1GjVN-XYYcfuen4t-rtUgWgW/s640/ZIKV+pathogenesis+blog.005.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Induction of the IFN response by ZIKV RNA</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Since
human placental trophoblasts (PHT) are resistant to infection with both ZIKV
FSS13025, a strain isolated in Cambodia and the original ZIKV MR766 strain,
ZIKV might induce an antiviral response similar to those observed in primary
human skin cells. Indeed, ZIKV infected PHT cells exhibit a high level of type
III Interferon, in particular Interferon-λ1 (IFNλ1) which is constitutively
expressed by PHT cells. Similar to primary skin fibroblast cells the expression
of OAS2, TLR3 and MX2 is unregulated when compared to human choriocarcinoma
JEG-3 that support ZIKV replication, suggesting that ZIKV induces identical
antiviral signaling pathways in both PHT and skin cells. Furthermore,
conditioned media from infected PHT cells inhibits the replication of ZIKV in
JEG-3 cells by inducing the expression of ISG, suggesting that PHT inhibit ZIKV
replication by inducing the expression in a autocrine and paracrine manner
although further work is needed verify the hypothesis. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">The
finding that ZIKV replication in PHT might be inhibited by IFNλ1 causes however some
problems in the utilization of mice as a model to investigate the potential relationship
between ZIKV and microcephaly in neonates and/or other embryonal development
defects since not only is there a difference in the morphology of the placenta
but also in the expression of IFNλ subtypes; mice only express IFNλ2 and IFNλ3
whereas PHT only low levels of IFNλ2 and no IFNλ3. </span><span lang="EN-GB" style="font-family: "helvetica";"><o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-GB" style="font-family: "helvetica"; mso-ansi-language: EN-GB;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The importance of the role
of the interferon response in controlling the replication of ZIKV and
preventing the onset of neurological symptoms resembling those observed in
infected humans is <span style="mso-spacerun: yes;"> </span>further strengthened by
studies using mice deficient for components of the interferon and comparing
them to fully immunocompetent mice. These experiments differ from those
conducted in Swiss albino mice described above in so far, as <span style="mso-spacerun: yes;"> </span>this model allows not only <span style="mso-spacerun: yes;"> </span>the use of wt ZIKV strains or ZIKV strains
that exhibit only low passage number in Vero or C6/36 mosquitoe cells but also prevents
the need of infection via intracelebral <span style="mso-spacerun: yes;"> </span>injection, thus avoiding the need for the
virus to cross the blood-brain barrier.<o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-GB" style="font-family: "helvetica"; mso-ansi-language: EN-GB;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to Swiss albino
mice injected i.c. with ZIKV 766, the injection of immunocompetent C57BL/6 5 to
6 week old mice with ZIKV MR766 or H/PF/2013 either s.c. or intravenous (i.v.)
does not induce the development of any neurological symptoms up to 10 days p.i.
nor weight loss. As mentioned above, the infection of immunocompetent mice 7
days of age with ZIKV Dakar however decreases survival by 33% at day 30 p.i. ,
suggesting that either age or route of infection might play a role in the
severity of the disease or alternatively that ZIKV strains of the African
lineage are more virulent than those of the Asian lineage.<o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";">In
order to determine </span><span lang="EN-GB" style="font-family: "helvetica"; mso-ansi-language: EN-GB;">if components of the interferon pathway prevent the
onset of symptoms and/or death of infected mice after the infection with ZIKV,
4-6 week old mice deficient for the transcription factors IRF3, IRF5 and IRF7
as well as deficient for the </span><span style="font-family: "helvetica"; mso-bidi-font-weight: bold;">Ubiquitin-like protein ISG15</span><span style="font-family: "helvetica"; mso-ansi-language: EN-GB;"> <span lang="EN-GB">were
infected with ZIKV MR766 or ZIKV H/PF/2013 i.v. or s.c. and monitored for signs
of infection for 10 days p.i. . In contrast to the single knockout mice, triple
knockout (TKO) IRF3 -/- IRF5 -/- IRF7 -/- mice exhibited symptoms such as
paralysis as early as 3 days p.i. regardless of the infection route. In
addition, up to 100% of infected TKO mice were dead 10 days p.i. whereas single
knockouts survived. In a similar way, single Ifnar-1 (Interferon-α receptor)
knockout mice infected with ZIKV Dakar 41519, ZIKV MR766 or ZIKV H/PF/2013
exhibited 100% mortality 10 days p.i. whereas infected single MAVS -/- knockout
mice did exhibit any mortality. Blocking the the IFNAR-1 receptor and thus IFN-
α/β using a monoclonal antibody one day prior ZIKV infection renders wt mice
susceptible to ZIKV which is similar to results described for West Nile Virus
(WNV), although blockage of IFNAR-1 does not increase mortality but induces
higher viral titres. Interestingly older Ifnar1 -/- mice exhibit a higher
survivial rate with 40-80% of infected mice despite weight loss; whether viral
loads are lower as well has not been investigated. <o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span lang="EN-GB" style="font-family: "helvetica"; mso-ansi-language: EN-GB;">Similar to ZIKV infected </span><span style="font-family: "helvetica";">A129 and AG129 mice, in Ifnar1 -/- mice the
tissues with the highest viral load are spleen, testes, kidneys, spinal cord,
brain and liver thus confirming previous reports that ZIKV is a
neurotropic virus. In addition, the brain and testes of surviving Ifnar1 -/-
exhibit high viral RNA levels<span style="mso-spacerun: yes;"> </span>up to 28
days p.i., a finding that might explain the occurrence of neurological symptoms as well as horizontal transmission of ZIKV to previously uninfected women. From the present epidemiological data however it is not clear if ZIKV induces encephalitis at a similar rate than those observed in patients infected with DENV or WNV.</span></span></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="font-family: "helvetica";"><br /></span></span></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="font-family: "helvetica";"><br /></span></span></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjVl_xcFJvIm9czrF-jgGbtB98ur7AU4TIGLedjJYjXCeensGK6vb6B9UnoS8QJH3aVy9Lu4uGQU3upt4-kXVFMXAUbJulf-RZFHU4oX3U6Fsq3ba1NyfIf2fJUM0kN4hidsl_oArEHXe9b/s1600/ZIKV+pathogenesis+blog.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjVl_xcFJvIm9czrF-jgGbtB98ur7AU4TIGLedjJYjXCeensGK6vb6B9UnoS8QJH3aVy9Lu4uGQU3upt4-kXVFMXAUbJulf-RZFHU4oX3U6Fsq3ba1NyfIf2fJUM0kN4hidsl_oArEHXe9b/s640/ZIKV+pathogenesis+blog.006.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Survival rates of immunocompetent and immunodeficient mice</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><span style="font-family: "helvetica";"><br /></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span lang="EN-GB" style="font-family: "helvetica"; mso-ansi-language: EN-GB;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Taken together with the
gene expression data obtained from JEG-3 and PHT cells, these results suggest
that the interferon response does protect not only placenta derived cells but
also mice from ZIKV induced death similar to WNV. Further data however are
needed if ZIKV neurovirulence in the embryo or foetus dependent on the
resistance of ZIKV to interferon induced signalling or due to the induction of
cell cycle arrest and subsequent apoptosis or neural progenitor cells. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<b style="mso-bidi-font-weight: normal;"><span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="mso-spacerun: yes;">
</span><span style="mso-spacerun: yes;"> </span>ZIKV in rhesus macaque monkeys<o:p></o:p></span></span></b></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In
general monkeys infected with ZIKV do not exhibit any or only mild clinical
signs of infections although virus can be detected as early as 3 days p.i. as
suggested by historic data.<o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";">In
order to assess the </span><span style="font-family: "helvetica"; mso-bidi-font-family: Verdana;">the infectivity of the original ZIKV MR766 isolate from Africa,
experiments are currently conducted at the University of Wisconsin-Madison that
determine the load of viral RNA in the blood, urine, saliva and cerebrospinal
fluid (CSF) <o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica"; mso-bidi-font-family: Verdana;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">of rhesus macaque monkeys infected with different
doses of ZIKV. In both experiments, 2 out of 3 animals exhibit maximum load
viral RNA in plasma at 3-5 days p.i. and in the urine at 7-9 days p.i. .<o:p></o:p></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhpfmHBmRAfhzaxGMgHZZwgJ5Yb2Xnf3ZrWqx-Fv4tI5Y7m3Q5E5DbZy2IhUUSNt3w6YpoymE7GLVFJMIDBhZxysBaxRd0ea8irWFwTw-L9f0E4W-zZ6R_pvQcXGhmnu0UtRXjF_R9sGPhc/s1600/ZIKV+pathogenesis+blog.007.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhpfmHBmRAfhzaxGMgHZZwgJ5Yb2Xnf3ZrWqx-Fv4tI5Y7m3Q5E5DbZy2IhUUSNt3w6YpoymE7GLVFJMIDBhZxysBaxRd0ea8irWFwTw-L9f0E4W-zZ6R_pvQcXGhmnu0UtRXjF_R9sGPhc/s640/ZIKV+pathogenesis+blog.007.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Load of viral RNA in rhesus macaque infected with ZIKV</td></tr>
</tbody></table>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In addition, similar studies are currently
performed to determine if the infection of monkeys with ZIKV induces the formation
of malformations in the brain during the foetal development, but as the time of
writing these studies have not concluded.</span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; mso-bidi-font-family: Verdana;">In conclusion, the infection of immunocompetent
mice with ZIKV is not lethal nor do those mice present themselves with clinical
symptoms such as paralysis. Mice deficient for interferon dependent antiviral
signaling however succumb to infection 10 days p.i., indicating that ZIKV is
not resistant to interferon signaling per se. In addition, in primary </span><span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">human placental trophoblasts ZIKV replication is
inhibited by IFNλ1, whereas previous studies suggest that human NPC and human
stem cells are supporting ZIKV replication. This suggests a model where ZIKV
needs to breach the placental-foetal barrier in order to infect embryonal cells
without infecting placental cells, suggesting that infected maternal cells need
to cross the barrier. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><o:p></o:p></span></span></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica"; mso-bidi-font-family: Verdana;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The activation of the interferon response by ZIKV
RNA however might not only induce antiviral signaling but also induce the up-
and downregulation of gene expression via inducing STAT1 and 2 mediated
signaling. In this model, STAT-1/-2 regulates the expression of genes encoding
for proteins regulating diverse processes as DNA repair, cell cycle control and
autophagy, thus contributing to cell death observed in infected hNPC as
<a href="http://virologytidbits.blogspot.com/2016/03/zika-virus-zikv-was-first-isolated-from.html" target="_blank">discussed before</a>. <o:p></o:p></span></span><br />
<span style="font-family: "helvetica"; mso-bidi-font-family: Verdana;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span style="font-family: "helvetica"; mso-bidi-font-family: Verdana;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj0j13I_88d36W5HDgCIXq19gMo0v2eVG5mbWPuO73zYmrRWzsTr7Bvxl3G3QUtbSlW9z5YL-yDUe0tgyjat_44xOR8FknlB66hcwVT3lvMgncYk9677ApMiEKvr9lc3Tj8IyUdIdoQ30Sn/s1600/ZIKV+pathogenesis+blog.008.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj0j13I_88d36W5HDgCIXq19gMo0v2eVG5mbWPuO73zYmrRWzsTr7Bvxl3G3QUtbSlW9z5YL-yDUe0tgyjat_44xOR8FknlB66hcwVT3lvMgncYk9677ApMiEKvr9lc3Tj8IyUdIdoQ30Sn/s640/ZIKV+pathogenesis+blog.008.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV RNA induces not only antiviral signalling but also regulates gene expression</td></tr>
</tbody></table>
<span style="font-family: "helvetica"; mso-bidi-font-family: Verdana;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span style="font-family: "helvetica"; mso-bidi-font-family: Verdana;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span style="font-family: "helvetica"; mso-bidi-font-family: Verdana;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span></div>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u><br /></u></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u>Further reading</u></span></span></div>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; text-align: justify;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Musso D, & Gubler DJ (2016). Zika Virus. <span style="font-style: italic;">Clinical microbiology reviews, 29</span> (3), 487-524 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27029595" rev="review">27029595</a></span></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large; text-align: justify;"> </span><br />
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Clinical+microbiology+reviews&rft_id=info%3Apmid%2F27029595&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus.&rft.issn=0893-8512&rft.date=2016&rft.volume=29&rft.issue=3&rft.spage=487&rft.epage=524&rft.artnum=&rft.au=Musso+D&rft.au=Gubler+DJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Antiviral+research&rft_id=info%3Apmid%2F26304704&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Animal+models+for+studying+dengue+pathogenesis+and+therapy.&rft.issn=0166-3542&rft.date=2015&rft.volume=123&rft.issue=&rft.spage=5&rft.epage=14&rft.artnum=&rft.au=Chan+KW&rft.au=Watanabe+S&rft.au=Kavishna+R&rft.au=Alonso+S&rft.au=Vasudevan+SG&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Chan KW, Watanabe S, Kavishna R, Alonso S, & Vasudevan SG (2015). Animal models for studying dengue pathogenesis and therapy. <span style="font-style: italic;">Antiviral research, 123</span>, 5-14 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26304704" rev="review">26304704</a></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Transactions+of+the+Royal+Society+of+Tropical+Medicine+and+Hygiene&rft_id=info%3Apmid%2F12995441&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus.+II.+Pathogenicity+and+physical+properties.&rft.issn=0035-9203&rft.date=1952&rft.volume=46&rft.issue=5&rft.spage=521&rft.epage=34&rft.artnum=&rft.au=DICK+GW&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Transactions+of+the+Royal+Society+of+Tropical+Medicine+and+Hygiene&rft_id=info%3Apmid%2F12995441&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus.+II.+Pathogenicity+and+physical+properties.&rft.issn=0035-9203&rft.date=1952&rft.volume=46&rft.issue=5&rft.spage=521&rft.epage=34&rft.artnum=&rft.au=DICK+GW&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">DICK GW (1952). Zika virus. II. Pathogenicity and physical properties. <span style="font-style: italic;">Transactions of the Royal Society of Tropical Medicine and Hygiene, 46</span> (5), 521-34 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12995441" rev="review">12995441</a></span> </span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+American+journal+of+tropical+medicine+and+hygiene&rft_id=info%3Apmid%2F27022155&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Characterization+of+a+Novel+Murine+Model+to+Study+Zika+Virus.&rft.issn=0002-9637&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Rossi+SL&rft.au=Tesh+RB&rft.au=Azar+SR&rft.au=Muruato+AE&rft.au=Hanley+KA&rft.au=Auguste+AJ&rft.au=Langsjoen+RM&rft.au=Paessler+S&rft.au=Vasilakis+N&rft.au=Weaver+SC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Rossi SL, Tesh RB, Azar SR, Muruato AE, Hanley KA, Auguste AJ, Langsjoen RM, Paessler S, Vasilakis N, & Weaver SC (2016). Characterization of a Novel Murine Model to Study Zika Virus. <span style="font-style: italic;">The American journal of tropical medicine and hygiene</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/27022155" rev="review">27022155</a></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+Host+%26+Microbe&rft_id=info%3Adoi%2F10.1016%2Fj.chom.2016.03.010&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=A+Mouse+Model+of+Zika+Virus+Pathogenesis&rft.issn=19313128&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1931312816301020&rft.au=Lazear%2C+H.&rft.au=Govero%2C+J.&rft.au=Smith%2C+A.&rft.au=Platt%2C+D.&rft.au=Fernandez%2C+E.&rft.au=Miner%2C+J.&rft.au=Diamond%2C+M.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+Host+%26+Microbe&rft_id=info%3Adoi%2F10.1016%2Fj.chom.2016.03.010&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=A+Mouse+Model+of+Zika+Virus+Pathogenesis&rft.issn=19313128&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1931312816301020&rft.au=Lazear%2C+H.&rft.au=Govero%2C+J.&rft.au=Smith%2C+A.&rft.au=Platt%2C+D.&rft.au=Fernandez%2C+E.&rft.au=Miner%2C+J.&rft.au=Diamond%2C+M.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Lazear, H., Govero, J., Smith, A., Platt, D., Fernandez, E., Miner, J., & Diamond, M. (2016). A Mouse Model of Zika Virus Pathogenesis <span style="font-style: italic;">Cell Host & Microbe</span> DOI: <a href="http://dx.doi.org/10.1016/j.chom.2016.03.010" rev="review">10.1016/j.chom.2016.03.010</a></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Archiv+fur+die+gesamte+Virusforschung&rft_id=info%3Apmid%2F5002906&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus+infection+of+the+central+nervous+system+of+mice.&rft.issn=0003-9012&rft.date=1971&rft.volume=35&rft.issue=2&rft.spage=183&rft.epage=93&rft.artnum=&rft.au=Bell+TM&rft.au=Field+EJ&rft.au=Narang+HK&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F26085147&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Biology+of+Zika+Virus+Infection+in+Human+Skin+Cells.&rft.issn=0022-538X&rft.date=2015&rft.volume=89&rft.issue=17&rft.spage=8880&rft.epage=96&rft.artnum=&rft.au=Hamel+R&rft.au=Dejarnac+O&rft.au=Wichit+S&rft.au=Ekchariyawat+P&rft.au=Neyret+A&rft.au=Luplertlop+N&rft.au=Perera-Lecoin+M&rft.au=Surasombatpattana+P&rft.au=Talignani+L&rft.au=Thomas+F&rft.au=Cao-Lormeau+VM&rft.au=Choumet+V&rft.au=Briant+L&rft.au=Despr%C3%A8s+P&rft.au=Amara+A&rft.au=Yssel+H&rft.au=Miss%C3%A9+D&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, Perera-Lecoin M, Surasombatpattana P, Talignani L, Thomas F, Cao-Lormeau VM, Choumet V, Briant L, Desprès P, Amara A, Yssel H, & Missé D (2015). Biology of Zika Virus Infection in Human Skin Cells. <span style="font-style: italic;">Journal of virology, 89</span> (17), 8880-96 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26085147" rev="review">26085147</a></span> </span><br />
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Archiv+fur+die+gesamte+Virusforschung&rft_id=info%3Apmid%2F5002906&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus+infection+of+the+central+nervous+system+of+mice.&rft.issn=0003-9012&rft.date=1971&rft.volume=35&rft.issue=2&rft.spage=183&rft.epage=93&rft.artnum=&rft.au=Bell+TM&rft.au=Field+EJ&rft.au=Narang+HK&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Bell TM, Field EJ, & Narang HK (1971). Zika virus infection of the central nervous system of mice. </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-style: italic;">Archiv fur die gesamte Virusforschung, 35</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> (2), 183-93 PMID: </span><a href="http://www.ncbi.nlm.nih.gov/pubmed/5002906" rev="review" style="font-family: 'helvetica neue', arial, helvetica, sans-serif;">5002906</a></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F26952870&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+Virus+Infects+Human+Cortical+Neural+Progenitors+and+Attenuates+Their+Growth.&rft.issn=1934-5909&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Tang+H&rft.au=Hammack+C&rft.au=Ogden+SC&rft.au=Wen+Z&rft.au=Qian+X&rft.au=Li+Y&rft.au=Yao+B&rft.au=Shin+J&rft.au=Zhang+F&rft.au=Lee+EM&rft.au=Christian+KM&rft.au=Didier+RA&rft.au=Jin+P&rft.au=Song+H&rft.au=Ming+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, Yao B, Shin J, Zhang F, Lee EM, Christian KM, Didier RA, Jin P, Song H, & Ming GL (2016). Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. <span style="font-style: italic;">Cell stem cell</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26952870" rev="review">26952870</a></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+stem+cell&rft_id=info%3Apmid%2F27038591&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Expression+Analysis+Highlights+AXL+as+a+Candidate+Zika+Virus+Entry+Receptor+in+Neural+Stem+Cells.&rft.issn=1934-5909&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Nowakowski+TJ&rft.au=Pollen+AA&rft.au=Di+Lullo+E&rft.au=Sandoval-Espinosa+C&rft.au=Bershteyn+M&rft.au=Kriegstein+AR&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Oncotarget&rft_id=info%3Apmid%2F26362401&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Interferon-regulatory+factor-1+%28IRF1%29+regulates+bevacizumab+induced+autophagy.&rft.issn=&rft.date=2015&rft.volume=6&rft.issue=31&rft.spage=31479&rft.epage=92&rft.artnum=&rft.au=Liang+J&rft.au=Piao+Y&rft.au=Henry+V&rft.au=Tiao+N&rft.au=de+Groot+JF&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Liang J, Piao Y, Henry V, Tiao N, & de Groot JF (2015). Interferon-regulatory factor-1 (IRF1) regulates bevacizumab induced autophagy. <span style="font-style: italic;">Oncotarget, 6</span> (31), 31479-92 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26362401" rev="review">26362401</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Science+translational+medicine&rft_id=info%3Apmid%2F25904743&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Interferon-%CE%BB+restricts+West+Nile+virus+neuroinvasion+by+tightening+the+blood-brain+barrier.&rft.issn=1946-6234&rft.date=2015&rft.volume=7&rft.issue=284&rft.spage=&rft.epage=&rft.artnum=&rft.au=Lazear+HM&rft.au=Daniels+BP&rft.au=Pinto+AK&rft.au=Huang+AC&rft.au=Vick+SC&rft.au=Doyle+SE&rft.au=Gale+M+Jr&rft.au=Klein+RS&rft.au=Diamond+MS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Lazear HM, Daniels BP, Pinto AK, Huang AC, Vick SC, Doyle SE, Gale M Jr, Klein RS, & Diamond MS (2015). Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier. <span style="font-style: italic;">Science translational medicine, 7</span> (284) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25904743" rev="review">25904743</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Assisted+Reproduction+and+Genetics&rft_id=info%3Adoi%2F10.1007%2Fs10815-016-0684-6&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus+infection+in+semen%3A+a+call+to+action+and+research&rft.issn=1058-0468&rft.date=2016&rft.volume=33&rft.issue=4&rft.spage=435&rft.epage=437&rft.artnum=http%3A%2F%2Flink.springer.com%2F10.1007%2Fs10815-016-0684-6&rft.au=Rowland%2C+A.&rft.au=Washington%2C+C.&rft.au=Sheffield%2C+J.&rft.au=Pardo-Villamizar%2C+C.&rft.au=Segars%2C+J.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Rowland, A., Washington, C., Sheffield, J., Pardo-Villamizar, C., & Segars, J. (2016). Zika virus infection in semen: a call to action and research <span style="font-style: italic;">Journal of Assisted Reproduction and Genetics, 33</span> (4), 435-437 DOI: <a href="http://dx.doi.org/10.1007/s10815-016-0684-6" rev="review">10.1007/s10815-016-0684-6</a></span></span></div>
thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-59017947649799552762016-03-08T15:49:00.001-05:002016-03-08T15:51:05.838-05:00Zika Virus induced mitotic arrest, apoptosis, DNA damage response and autophagy: recipe for disaster? <br />
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<span style="-webkit-font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Zika Virus (ZIKV) was first isolated from monkeys in 1947 and until 2007 only isolated cases of infection in humans were reported although serologic studies suggested widespread distribution in Africa and Southeast Asia. In 2007 however ZIKV of the Asian lineage caused an outbreak in Yap/Federal Micronesia followed by an outbreak in French Polynesia in 2013 and the current outbreak in Central & South America and the Caribbean. ZIKV is mainly transmitted via infected <i>Aedes spp.</i>mosquitoes but sexual transmission via semen of infected man has also been reported in addition to contaminated blood and blood products. </span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-kerning: none;">Clinical symptoms caused by ZIKV infection are very similar to that of other arboviral infections such as Dengue Virus (DENV) or Chikungunya Virus (CHIKV) which often co-circulate in areas affected by ZIKV and more often than not ZIKV infection is asymptomatic. In general, ZIKV may cause fever, maculopapular rash, and arthralgia or conjunctivitis. Following the outbreak in French Polynesia 2013 -2014 an increase in Guillain</span><span style="-webkit-font-kerning: none; -webkit-text-stroke-color: rgb(84, 84, 84); color: #545454;">-</span><span style="font-kerning: none;">Barré Syndrome (GBS) has been observed (albeit only by retrospective analysis) and -based on data obtained during the current outbreak-a link between the onset of microcephaly and ZIKV infection during the early stages of gestation has been proposed (but not verified).</span></span></div>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Experimentally, the neurotrophic properties of ZIKV have been demonstrated in mice injected with mouse adapted strain of ZIKV intraperitoneally and a isolates directly of obtained from monkeys that were injected intracelebral. In both cases, virus replicated in neuronal cells of the CNS and the brain with extensive apoptosis of infected cells. A subtraction of infected mice also showed paralysis or morbidity, suggesting that in mice ZIKV can induce a severe infection. Cerebrospinal fluid from GBS patients has been shown to induce neuronal apoptosis suggesting the presence of neurotic factors, but at present this has not been confirmed to be the case for ZIKV induced GBS and the relevance to disease pathology is unclear. In the case of ZIKV induced microcephaly, ZIKV may be transmitted to the embryo and/or foetus and interfering with brain development via the placenta. Indeed, ZIKV has been isolated in the placenta of ZIKV positive pregnant women, suggesting that ZIKV might be transmitted via exosomes (similiar to HCV) that infect embryonic and/or foetal cells of the neuroepithelium or directly infects the cerebral cortex during the earliest stages of brain development. Alternatively, ZIKV infection of the placenta disrupts the outer layer of the placenta thus inducing either miscarriage or -in the absence of viral induced miscarriage- contribute to viral induced microcephaly by disrupting placental signals to the developing brain and inducing an inflammatory response with the developing foetus (similar to MHV-68). In any case, ZIKV has been detected both in the amniotic fluid of at least two pregnant women whose foetuses were diagnosed with microcephaly as well as in foetal brain tissue, suggesting that the currently circulating ZIKV strains are indeed neurotrophic and might contribute to the onset of microcephaly. </span></span></div>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Experimentally, younger mice infected with ZIKV derived from monkey exhibit more severe brain damage compared to older mice suggesting that ZIKV indeed might indeed interfere with the developing brain. Human induced pluripotent stem cells differentiated into forebrain specific human neural progenitor cells (hNPC) that have been infected with the original ZIKV strain MR766 used in the mice studies published in 1952 , suggest that ZIKV induces cell cycle arrest and apoptosis (and subsequent growth arrest) 72 hrs p.i. . </span></span></div>
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<span style="-webkit-font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="-webkit-text-stroke-width: initial;">Gene expression analysis of ZIKV infected hNPC showed that ZIKV infection alters the expression of at least 7000 genes related to cell cycle regulation, the DNA damage response, autophagy, apoptosis and other </span>cellular<span style="-webkit-text-stroke-width: initial;"> processes suggesting that ZIKV might indeed interfere with these pathways as discussed before and as detailed below. In general, ZIKV infection downregulates the expression of genes encoding for proteins regulating DNA repair and cell cycle progression whilst upregulating the expression of genes ending for proteins regulating autophagy and the ER stress response, suggesting that ZIKV induces the formation of stalled replication forks, inhibiting the progression of S to G2 phase, inducing mitotic arrest whilst promoting the formation of lipid droplets and autophagosome-like vesicles thus supporting viral replication and dissemination. </span></span></span></div>
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<b style="-webkit-text-stroke-width: initial; font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"><span style="font-size: large;">ZIKV: inhibition of DDR, DNA replication and the cell cycle </span></b></div>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">As discussed <a href="http://virologytidbits.blogspot.com/2016/03/positive-strand-rna-viruses-and-ddr.html" target="_blank">before</a>, both retroviruses and positive strand RNA viruses (in addition to DNA viruses interfere with the DNA damage response which can be induced by the expression of viral proteins, endogenous reactive oxygen species or by exogenous agents including UV and chemotherapeutic drugs. Depending on the nature of the DNA damage, different repair pathways can be induced, with the homologous DNA repair pathway (HR) predominant in S and G2 cells and the Non-Homologous End Joining (NHEJ; which itself can be distinguished between a conservative and alternative pathway) present in all phases of the cell cycle, (probably) including M phase. Upon successful DNA repair, cells reenter the cell cycle whereas incomplete DNA repair can induce an arrest in S phase and subsequent G2 arrest; failure to activate the G2/M checkpoint may result in mitotic arrest followed by apoptosis or abberant mitosis, thus contributing to the development of tumour cells. </span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhHgStxoxvgqYs5m2mVObLkVFjYU-RAG31dCOxgEYY6w6K7JukJfNBPutcTRVEuGygvoIwlTerfC_lOMI5YXNAkBxBvmZz3UbR5SJIZUs-KCmUZ8oqC7ixflAtZ3JEE61CshW1oJNYedouL/s1600/Blog+ZIKV+DDR+Autophagy+Cell+cycle.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhHgStxoxvgqYs5m2mVObLkVFjYU-RAG31dCOxgEYY6w6K7JukJfNBPutcTRVEuGygvoIwlTerfC_lOMI5YXNAkBxBvmZz3UbR5SJIZUs-KCmUZ8oqC7ixflAtZ3JEE61CshW1oJNYedouL/s640/Blog+ZIKV+DDR+Autophagy+Cell+cycle.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: General outline of the connection between the DNA damage response, cell cycle regulation and<br />
autophagy</td></tr>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In the case of positive RNA viruses, the expression of IBV and SARS nsp13 protein has been shown to induce stalled replication forks and the expression of the N protein derived from different Coronaviruses has been shown to delay the progression from S to G2 probably by inducing ATR (and thus potentially the ATR dependent DNA damage response). Delaying the onset of G2 might favour viral replication not only by extending G2 and thus providing enough time to replicate but also provide cellular resources such as enzymes or nucleotides required for viral replication. Failure to resolve DNA damage that naturally occurs during DNA replication or persistent activation of the DDR by viral proteins however might contribute also to mitotic arrest and thus induce apoptosis.</span></span></div>
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<tr><td class="tr-caption" style="text-align: center;">Table: Genes that are down-or unregulated in ZIKV infected cells: DDR</td></tr>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In the case of ZIKV infected hNPC, viral infection decreases the expression of genes encoding proteins that are required for at least three distinct pathways, namely HR dependent pathways induced by both ATM and ATR, as well as the POLQ dependent Base-Excision Repair (BER) pathway and the Fanconi Anemia (FA) pathway that intersects with the ATR pathway. In contrast to the decreasing the expression of genes related to the main DNA damage repair pathways, the expression of at least one gene, STKL18, related to the Nucleotide Excision Repair and a NBS1 independent repair pathway, ATMIN, is increased following ZIKV infection. The relative contribution of these pathways to DNA repair in general are however minor and if these pathways are functional in ZIKV infected cells is not known presently. </span></span></div>
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<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV potentially inhibits the DDR at multiple sites whilst inducing the acetylation of NBS1 and<br />
the initial recruitment of sensors to sites of DNA damage induced by stalled DNA replication</td></tr>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to genes encoding proteins regulating the DDR, the expression of genes encoding proteins regulating the cell cycle, in particular genes related to the progression of G1, G1 to S, S to G2 and those related to the control of mitotic progression and chromosome segregation, are generally downregulated with the notable exception of NEDD1. Since NEDD1 encodes for a protein involved in the duplication of the centriole and spindle assembly, it might be possible that the over expression of NEDD-1 induced by ZIKV infection might induce mitotic arrest due to the presence of multiple centrioles. In addition to genes encoding for proteins such as Cyclin B1, CDK2, or CDC25A, ZIKV expression also downregulates the expression of genes related to DNA replication, suggesting that ZIKV infection might also induce the formation of stalled replication forks, which could be measured experimentally using a CldU/IdU based assay.</span></span></div>
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<span style="-webkit-text-stroke-width: initial; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Consequently, it can be assumed that ZIKV infection induces the arrest of infected cells in G2 and/or M phase of the cell cycle -which is supported by flow cytometry based cell cycle analysis of infected hNPC cells. Using Histone H3-P(Ser-10) as a marker for mitotic cells it should be easy to discriminate cells arrested in G2 from cells arrested in M phase. Confocal microscopy can be used to further distinguish cells arrested in prophase from those in metaphase or anaphase. Based on the data obtained from analysing the transcriptome, it might be however possible that ZIKV arrests cells in multiple stages of mitosis, since not only the formation of spindle poles might be affected but also the progression of anaphase and thus the onset of telophase.</span><span style="-webkit-text-stroke-width: initial; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> </span></div>
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<tr><td class="tr-caption" style="text-align: center;">Table: Genes down- or upregulated in ZIKV infected cells: cell cycle</td></tr>
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<tr><td class="tr-caption" style="text-align: center;">Figure: Cell Cycle arrest in ZIKV infected cells </td></tr>
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<span style="font-kerning: none;"><b><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">ZIKV: promotion of autophagosome formation, ER stress response and lipid droplet formation</span></b></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-kerning: none;">In contrast to genes related to the control of the cell cycle, the DDR and DNA replication, ZIKV infection generally induces the expression of genes encoding for proteins required for the initiation of autophagosome formation including those encoding for proteins that increase the pool of cytosolic LC3 (SIRT1 and ATG4A) or induce the formation of autophagosomes (STK38L, ATG16L1, RABGAP1 and ULK1)</span><span style="-webkit-font-kerning: none; line-height: normal;"> </span><span style="font-kerning: none;">whereas selective (p62/SQSTM-1 dependent) autophagy is inhibited maybe due to decreasing the expression of KLF4 and stress induced autophagy by decreasing the expression of Caspase-2. The maturation of the autophagosome and/or lysosome however might be inhibited by decreasing the expression of LAMP2, similar to the formation of antiviral autophagic clusters by decreasing the expression of ISG15. </span></span></div>
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<tr><td class="tr-caption" style="text-align: center;">Table: Genes are down-orupregualted in ZIKV infected cells: Autophagy and UPR</td></tr>
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<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV inhibits selective autophagy whilst promoting the formation of viral RC via increased autophagosome/EDEMosome formation</td></tr>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Increasing the expression of Optineurin and BNIP-3 might promote the formation of mitophagsomes and thus lipophagy as described before. The synthesis of lipid droplets at the ER might be aided by increased expression of DCP2 and XRN1, and similar to cells infected with HCV, ZIKV might promote the formation of ER localised lipid droplets by decreasing the number of P-bodies whilst decreasing the formation of stress granules. </span></span></div>
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<tr><td class="tr-caption" style="text-align: center;">Figure: Lipid droplets are degraded via ZIKV induced mitophagy</td></tr>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The formation of lipid droplets and autophagosomes in ZIKV infected cells might also be supported by increasing the expression of proteins regulating the ER stress response/Unfolded Protein Response (UPR) such as SEC16A (inducing the formation of COPII vesicles) and EDEM1 (inducing EDEMosomes). In the case of BNIP-3, increased BNIP-3 might either induce mitophagy or induce the release of Ca2+ from the ER and thus promote mitochondrial apoptosis; alternatively BNIP-3 might induce the depolarisation whilst the Optineurin facilitates the clearance of damaged mitochondria by mitophagy. </span></span></div>
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<span style="-webkit-text-stroke-width: initial; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The induction go both the PERK and IRE-1 induced ER stress however might be inhibited, thus preventing -at least partially- the induction of UPR induced apoptosis. In contrast, only the ATF mediated ER stress response might be still active, resulting in delayed or decreased expression of CHOP.</span><span style="-webkit-text-stroke-width: initial; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> </span></div>
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<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV and the ER stress response</td></tr>
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<span style="font-kerning: none;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In summary, ZIKV might induce the formation of autophagosomes or autophagosome-like structures by inducing the expression of proteins that are known inducers of autophagosome formation as well as inducing at least a partial ER stress response whilst inhibit selective autophagy. The formation of autophagosomes and the inhibition of p62/SQSTM-1 dependent selective autophagy has been confirmed in skin fibroblasts and keratinocytes whilst the induction of the UPR by ZIKV has not been demonstrated yet. In addition to inducing autophagosomes, the formation of antiviral clusters might be inhibited,similar to neuronal cells infected with Yellow Fever Virus, probably due to the downregulation of both ISG15 and p62/SQSTM-1 expression. Propagation of lipid droplet formation and lipophagy by decreasing the number of P bodies and promoting the formation of mitophagosomes fused with LD's might promote viral replication by providing free fatty acids but probably not by providing a scaffold for the viral replication complex (in contrast to HCV). If the upregulation of SEC16A contributes to the release of exsomes containing viral particles similar to HCV remains also to be seen. </span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgnTskJaxHUFjSI0pn21aIvHGIiY5Oz0YIfIArVPaVvpzTEbRO4YR0783zrdlwkS5ZrMA1u3Bad8TxkY7Co0o47lwJxQNCDQ2keZ3ZsazVDNcT-wKhHVDe_qZn3VbQlCVZJIxIxfgyxHXhc/s1600/Blog+ZIKV+DDR+Autophagy+Cell+cycle.012.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgnTskJaxHUFjSI0pn21aIvHGIiY5Oz0YIfIArVPaVvpzTEbRO4YR0783zrdlwkS5ZrMA1u3Bad8TxkY7Co0o47lwJxQNCDQ2keZ3ZsazVDNcT-wKhHVDe_qZn3VbQlCVZJIxIxfgyxHXhc/s640/Blog+ZIKV+DDR+Autophagy+Cell+cycle.012.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV induced pathways are linked, controlling cell proliferation in multiple<br />
ways</td></tr>
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<span style="-webkit-text-stroke-width: initial; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In conclusion, ZIKV induces apoptosis by regulating by generally downregulating the expression of genes encoding proteins that regulate the replication of cellular DNA, the DNA damage response and the cell cycle as well as upregulating genes expressing proteins that are proapoptotic (DIABLO and FADD). Apoptosis is therefore induced by an arrest in G2 and M phase of the cell cycle as well as promoting the depolarisation of mitochondria. Inducing the expression of genes that promote autophagosome formation as well as formation and degradation of lipid droplets in contrast promotes viral replication.</span><span style="-webkit-text-stroke-width: initial; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The spatial expression pattern of these genes however remains to be elucidated, but in general the analysis of the transcriptome on ZIKV infected hNPC cells provides an insight in the complex interaction of the various pathways regulated by ZIKV and ZIKV related viruses. </span></div>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Transactions+of+the+Royal+Society+of+Tropical+Medicine+and+Hygiene&rft_id=info%3Apmid%2F12995440&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus.+I.+Isolations+and+serological+specificity.&rft.issn=0035-9203&rft.date=1952&rft.volume=46&rft.issue=5&rft.spage=509&rft.epage=20&rft.artnum=&rft.au=DICK+GW&rft.au=KITCHEN+SF&rft.au=HADDOW+AJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Transactions+of+the+Royal+Society+of+Tropical+Medicine+and+Hygiene&rft_id=info%3Apmid%2F12995440&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus.+I.+Isolations+and+serological+specificity.&rft.issn=0035-9203&rft.date=1952&rft.volume=46&rft.issue=5&rft.spage=509&rft.epage=20&rft.artnum=&rft.au=DICK+GW&rft.au=KITCHEN+SF&rft.au=HADDOW+AJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">DICK GW, KITCHEN SF, & HADDOW AJ (1952). Zika virus. I. Isolations and serological specificity. <span style="font-style: italic;">Transactions of the Royal Society of Tropical Medicine and Hygiene, 46</span> (5), 509-20 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12995440" rev="review">12995440</a></span></span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> </span></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F26937026&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Hepatitis+C+Virus+Exploitation+of+Processing+Bodies.&rft.issn=0022-538X&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Biegel+JM&rft.au=Pager+CT&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Biegel JM, & Pager CT (2016). Hepatitis C Virus Exploitation of Processing Bodies. <span style="font-style: italic;">Journal of virology</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26937026" rev="review">26937026</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Biomolecules&rft_id=info%3Apmid%2F26751489&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Activation+of+the+DNA+Damage+Response+by+RNA+Viruses.&rft.issn=&rft.date=2016&rft.volume=6&rft.issue=1&rft.spage=&rft.epage=&rft.artnum=&rft.au=Ryan+EL&rft.au=Hollingworth+R&rft.au=Grand+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology">Ryan EL, Hollingworth R, & Grand RJ (2016). Activation of the DNA Damage Response by RNA Viruses. <span style="font-style: italic;">Biomolecules, 6</span> (1) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26751489" rev="review">26751489</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Biochemical+and+biophysical+research+communications&rft_id=info%3Apmid%2F25912875&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=NDR1+modulates+the+UV-induced+DNA-damage+checkpoint+and%C2%A0nucleotide+excision+repair.&rft.issn=0006-291X&rft.date=2015&rft.volume=461&rft.issue=3&rft.spage=543&rft.epage=8&rft.artnum=&rft.au=Park+JM&rft.au=Choi+JY&rft.au=Yi+JM&rft.au=Chung+JW&rft.au=Leem+SH&rft.au=Koh+SS&rft.au=Kang+TH&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Park JM, Choi JY, Yi JM, Chung JW, Leem SH, Koh SS, & Kang TH (2015). NDR1 modulates the UV-induced DNA-damage checkpoint and nucleotide excision repair. <span style="font-style: italic;">Biochemical and biophysical research communications, 461</span> (3), 543-8 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25912875" rev="review">25912875</a></span>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-68085479586732546742016-03-02T15:23:00.001-05:002016-03-02T15:23:21.096-05:00Positive strand RNA viruses and the DDR: cell cycle arrest and autophagy <div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Both DNA and RNA viruses are dependent of cell
proliferation for replication. Thus viruses often posses proteins which are
able to interact with cellular proteins which are responsible for maintaining
the regulation of the cell cycle. In general viruses could either slow the cell
cycle or activate the cell cycle.</span></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiJ7k5gj-xVxAXg7d5KbdQj92JHbZ1x_TfMP2MGv04wnNS8NHcGwxAVwi_A_nQI6eIKG3siYHIUWl0-NpyzcaVtKyU0o0U2aUeWhMfwq0KH3m8okZgSAuAbtBAVd1TK71mVin-J1Zz4xXgB/s1600/RNA+viruses+and+DDR.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiJ7k5gj-xVxAXg7d5KbdQj92JHbZ1x_TfMP2MGv04wnNS8NHcGwxAVwi_A_nQI6eIKG3siYHIUWl0-NpyzcaVtKyU0o0U2aUeWhMfwq0KH3m8okZgSAuAbtBAVd1TK71mVin-J1Zz4xXgB/s640/RNA+viruses+and+DDR.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Viruses and the DDR: multiple points of action</td></tr>
</tbody></table>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">In the case of HIV-1, the viral R protein (VpR ) was
identified to be responsible for accumulation of<span style="mso-spacerun: yes;"> </span>G2 arrested cells. by preventing the
activation of<span style="mso-spacerun: yes;"> </span>the cyclinB/CDK 1 through
the inhibition of a phosphatase, cdc25A, and the activation of a kinase, Wee1. Both
enzymes are hypophosphorylated in HIV-1 infected cells and VpR may act through
the activation of protein phosphatase 2A (PP2A) </span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">and thus blocks the G2-M
transition. In this context it is very interesting to note that VpR -similar to
coronaviral N protein is also located in the nucleolus of the cell. Another
example is the paramyxovirus Simian parainfluenza virus 5, which is able to
slow the progression both G1 into S and G2 into M but not of a G1 or G2 arrest
.The V protein of Simian Virus 5 binds to a protein involved in DNA repair,
DDB1 (DNA damage binding protein). DDB1 becomes activated upon binding through
V. Activation of<span style="mso-spacerun: yes;"> </span>DDB1 in turn leads to
slowing the progression of G2 into M and binds to the Retinoblastoma protein
and thus prevents entering of the S phase through non-activation of E2F.
Because of the delayed activation of E2F, the transactivation of the genes
necessary for successful entry into the S phase is also delayed.<o:p></o:p></span></span></div>
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<b><span lang="EN-US"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Coronavirus and the cell cycle: Induction of p53 by
ATR induces S phase arrest</span></span></b></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">The expression of the nucleocapsid (N) protein of
Infectious Bronchitis Virus (IBV) or Severe Acute Respiratory Syndrome Virus
(SARS) in Vero cells decreases not only cell proliferation in the absence of
apoptosis but also arrests the cell cycle at S phase as well as inducing in a
significant number of cells a mitotic defect as indicated by the presence of a
cleavage furrow.<span style="mso-spacerun: yes;"> </span></span></span></div>
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<tr><td class="tr-caption" style="text-align: center;">Figure: Localisation of Coronavirus N protein and mitotic arrest</td></tr>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><br /></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Indeed, bivariate flow
cytometry of BrdU incorporation and Propidium iodide content and subsequent dot
plot analysis by gating for G0/G1, S and G2/M phase showed that the number of
cells in S phase increased by 20% if the cells were transfected with IBV N
compared to mock transfected or cells transfected with empty vector as well as
an increase in cells with DNA content higher than 4n,indicating not only that
the expression of IBV N delays the cell cycle but also might induce mitotic
defects. Similar the cell cycle is delayed in Vero cells arrested in G2/M with
Nocadazole and released for 24 hrs by replacing the Nocadazole containing
medium with fresh DMEM, indicating that the expression of N in Vero cells does
delay the progression of Vero cells from S phase into G2 phase of the cell
cycle. In Vero cells infected with a Vero adapted IBV Beaudette US strain a
similar delay can also be observed (albeit to a lower extent) indicating that
viral replication does not antagonise the ability of N to delay the cell cycle.
In contrast to Vero cells, the expression of IBV N in Saos-2 cells that are
deficient for p53 does not induce a delay or arrest in the cell cycle
indicating that p53 is required for inducing the observed delay in cell cycle
progression. <o:p></o:p></span></span></div>
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<tr><td class="tr-caption" style="text-align: center;">Figure: Expression of IBV N in Vero cells but not in Saos-2 cells induces cell cycle arrest<br />that it can be abrogated by Caffeine<br /></td></tr>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span lang="EN-US" style="color: black;">p53 can be activated by ATR as a result of nucleolar
stress and since the expression of the expression of the coronaviral N protein
has been proposed to induce nucleolar stress, treatment of cells transfected
with SARS or IBV N with an inhibitor of ATR should therefore reverse the
activation of p53 by ATR. Indeed, Vero cells transfected with either IBV or SARS
N protein</span><span lang="EN-US" style="color: #fb0207;"> </span><span lang="EN-US" style="color: black;">and treated with 4 mM Caffeine do not exhibit an
increase in S phase<span style="mso-spacerun: yes;"> </span>-indicating that N
protein induced S phase arrest is indeed mediated by an activation of ATR- but
instead exhibit an increase in G0/G1 phase of the cell cycle indicating that N
inhibits the progression of cells from G1 into S phase. Indeed, the expression
of N does not only induce nucleolar stress but also inhibits Cyclin D1 as well
as Cyclin A and E thus inhibiting entry into S phase in cells treated with
Caffeine. <o:p></o:p></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0Lc3PDGxmXRNFnT17Cz66WYxjzxraU4Zeg83F1vZzT-FgnsefA-e0hJQq-EFzaOlyujeztQ8sLHPjSMeHp56j8D06_8jkYI3nd7ITZItCkCCdgxGHpiwm2Msees65tPud4AFDhkSJ3nJJ/s1600/RNA+viruses+and+DDR.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0Lc3PDGxmXRNFnT17Cz66WYxjzxraU4Zeg83F1vZzT-FgnsefA-e0hJQq-EFzaOlyujeztQ8sLHPjSMeHp56j8D06_8jkYI3nd7ITZItCkCCdgxGHpiwm2Msees65tPud4AFDhkSJ3nJJ/s640/RNA+viruses+and+DDR.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: The expression of SARS N in A549 cells induces a transient<br />arrest in S phase</td></tr>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">In addition, Caffeine treatment of Vero cells
transfected with IBV N also increases the percentage of cells in G2/M
indicating the activation of the G2/M checkpoint and flow cytometry analysis of
Caffeine treated Vero cells transfected with SARS N confirms that the
expression of SARS N induces a G2 rather than a mitotic arrest since SARS N
does not increase Histone H3(Ser-10) phosphorylation. <o:p></o:p></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">In conclusion, the expression of IBV and SARS N
induces an arrest primary in S phase of the cell cycle that is at least partially
dependent on the induction of p53 by ATR. Abrogation of ATR dependent cell
cycle arrest induces an arrest in late G1/early S phase and an arrest in G2
-but not M- phase. <o:p></o:p></span></span></div>
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<tr><td class="tr-caption" style="text-align: center;">Figure: The expression of SARS N in Vero cells induces p53 (A), p21 (B), CHK-1 (C) and but not mitotic arrest (D)</td></tr>
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<span style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">As discussed before, the expression of N might induce
DRAM-1 and thus autophagy as a result of nucleolar stress that might promote
viral replication by promoting the formation of viral replication centres.</span><span style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif;"> </span><span style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">In budding yeast, ATR mediated induction of
autophagy has been linked to the induction of anaphase and recent evidence suggests
that LC3 positive structures -probably mitophagosomes- are present throughout
mitosis. Induction of autophagy by N therefore might be responsible for a
premature onset of anaphase and thus inducing the formation of the midbody.
Since aberrant cytokinesis is only present in a subset of cells expressing N,
the majority of cells might not undergo premature mitosis but instead, the
induction of autophagy might be a contributing factor to N induced S-G2/M
arrest since autophagy can arrest cells by increasing levels of phosphorylated
Cdc2(Y15), Cyclin A, E and B1, and Rb (S807/811) and decreasing Cyclin D1.
Furthermore, Coronavirus N induced autophagy might also attenuate the DNA
damage response by degrading Chk-1 via chaperone-mediated autophagy.</span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">In addition to N, the expression of IBV and SARS
nsp-13 has been shown to induce the DNA damage response as well as inducing S
phase arrest via ATR. In this case, ATR is activated by stalled replication
forks due to the inhibition of<span style="mso-spacerun: yes;"> </span>p125
subunit of DNA polymerase δ and -similar to IBV and SARS N- the activation of
p53 might induce autophagy. Since nsp-13 localises both to the nucleus and the
cytoplasm, nsp-13 might trigger distinct events at different times of the viral
replication cycle. ER localised nsp-13 might trigger the ER stress response and
akin to (and maybe in addition to) nsp-4 and -6, promote the formation of viral
RC by initiating the formation of omegasome-like structures. Nuclear nsp-13 in
contrast inhibits DNA replication and induces the ATR response which in turn
might facilitate the formation of RC indirectly by inducing the formation of
autophagosomes and/or by inducing a S-G2/M arrest thus preventing degradation
of the viral genome during mitosis as well as extending the cell cycle to allow
viral replication. The individual contributions of both N and nsp-13 are
however not known and it remains to be seen if the localisation of nsp-13 is
altered during viral replication, i.e. if nsp-13 undergoes nuclear-cytoplasmic
shuttling. It should also be noted that the expression of SARS N induces the
activation of caspase-3 in the absence of depolarised mitochondria and in the
absence of apoptosis. N and/or nsp-13 induced autophagy therefore might also
promote the degradation of proapoptotic proteins or promote mitophagy and thus
prevent Coronavirus induced apoptosis in addition to promoting the formation of
viral RC. Interestingly, activated Caspase-3 localises to the nucleolus in A549
cells transfected with SARS N without -as indicated by staining of SARS N
transfected cells with HSP-60 and Bcl-2 as well as flow cytometry detection of
activated Bax- the presence of damaged mitochondria.<o:p></o:p></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhS2SDs9gubOtlUnc3FSo65QITGUg96EgKNnr21BVusN7bEQ_zJOA9PUGtPIL9s6U9IDv0-hV8XPQmuj3GeVR82uH3vSU6oEs_IL6xT_nIquA-nvqZg1hB5KRtvM4HDGr2KlpkJmBPRP5Xw/s1600/RNA+viruses+and+DDR.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhS2SDs9gubOtlUnc3FSo65QITGUg96EgKNnr21BVusN7bEQ_zJOA9PUGtPIL9s6U9IDv0-hV8XPQmuj3GeVR82uH3vSU6oEs_IL6xT_nIquA-nvqZg1hB5KRtvM4HDGr2KlpkJmBPRP5Xw/s640/RNA+viruses+and+DDR.006.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: SARS N induces the localisation of active Caspase-3 to the nucleolus</td></tr>
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<tr><td class="tr-caption" style="text-align: center;">Figure: Activity of Caspase-3 is not impaired in A549 cells transfected<br />with SARS N</td></tr>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><br /></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><br /></span></span></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhnwbMaAWwY7HdPy4Q8l6kK8wGK9bnbYab54tipHRoxtKjv8sik1HYmMLVIXqbgCpeXGOSGX0fsO4lVcHtZj0vO-_-MdR5zvindUNbbZl6yFII240uIRbNrW_XQXM9LMZfpxxZW88xXWRe_/s1600/RNA+viruses+and+DDR.008.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhnwbMaAWwY7HdPy4Q8l6kK8wGK9bnbYab54tipHRoxtKjv8sik1HYmMLVIXqbgCpeXGOSGX0fsO4lVcHtZj0vO-_-MdR5zvindUNbbZl6yFII240uIRbNrW_XQXM9LMZfpxxZW88xXWRe_/s640/RNA+viruses+and+DDR.008.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: SARS N does not impair mitochondrial integrity in A549 cells</td></tr>
</tbody></table>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><br /></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">In human MRC-7 cells the disintegration of the
nucleolus has been shown to precede cell cycle arrest and p53 activation, suggesting
that the nucleolar localisation of active Caspase-3 might contribute to
nucleolar stress induced by the expression of SARS-CoV N protein, but further
studies are needed to determine the pathway of caspase-3 activation and if
damaged mitochondria are degraded by mitophagy. Also, it has to be determined
of the induction of ATR by N or any other coronaviral protein does prevent the
activation of caspase-3 dependent apoptosis. Alternatively, the expression of
nsp-13 or N might induce the ER stress response and thus protects cells from
caspase-3 dependent apoptosis. <o:p></o:p></span></span></div>
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<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">In conclusion, both the expression of N and nsp-13
induces the ATR dependent DNA damage response as well might prevent the
execution of the DDR by abrogating downstream signaling pathways thus arresting
cells in S and/or G2 phase of the cell cycle. In the case of N, inhibition of
G1 and S phase cyclins, namely Cyclin D1, A, and E, contributes to the observed
arrest. The induction of p53 via ATR by N or nsp-13 might however contribute to
the induction of Interferon type I signaling, which can be counteracted by the
expression of the<span style="mso-spacerun: yes;"> </span>PLP2 catalytic domain
of nsp-3 . PLP2 therefore might not only inhibit antiviral singling but also
partially prevent N induced cell cycle arrest, namely pathways induced by p53
such as the degradation of CHK-1 and the increase of Cyclin E m A, and B as
well as the decrease of Cyclin D1, thus preventing S phase arrest in addition
to prevent mitotic defects. So far however this has not been experimentally
been proven. <o:p></o:p></span></span></div>
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<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEin4a6sBLxdyuqeBdOzFEF4sJj4pge1vz6agdB6jId3Z3E2eRpX1ssRTcBurlniPVDqA9zq7UqlarauTDIcb5ZmhjFL1gQmVFfSsv0pc6SVp__v41sPcsxBjIPF-iDXidhfkLQIm0hzS-Y8/s1600/RNA+viruses+and+DDR.009.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEin4a6sBLxdyuqeBdOzFEF4sJj4pge1vz6agdB6jId3Z3E2eRpX1ssRTcBurlniPVDqA9zq7UqlarauTDIcb5ZmhjFL1gQmVFfSsv0pc6SVp__v41sPcsxBjIPF-iDXidhfkLQIm0hzS-Y8/s640/RNA+viruses+and+DDR.009.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: IBV N, nsp-13, and nsp-14: induction of ATR and ATM dependent pathways</td></tr>
</tbody></table>
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Furthermore, it needs to be determined why the
expression of the TGEV N protein in contrast to the N protein derived from IBV,
SARS, or MHV does induce p53 dependent apoptosis. Similar to SARS N, TGEV N
induces a cell cycle arrest (in S and G2/M) and the activation of Caspase-3;
unlike in A549 cells expressing SARS N however, Bax translocates to the
mitochondria and induces the depolarisation of the mitochondrial membrane. It
might be possible that in PK-15 autophagy is impaired and damaged mitochondria
might accumulate. One possibility is that both SARS and IBV N do increase the
expression of both Bak and Mcl-1 whereas TGEV N does not. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
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<span lang="EN-US" style="color: black;"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Finally, it needs to be determined if the nucleolar
localisation of other viral proteins such as the core protein of JEV induces
the activation of ATR as a result of nucleolar stress. </span><span style="font-family: Helvetica;"><o:p></o:p></span></span></div>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"></span><br />
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span>
<div style="text-align: justify;">
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><u>Further reading</u></span></span></div>
<div style="text-align: justify;">
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span></div>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><div style="text-align: justify;">
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Trends+in+biochemical+sciences&rft_id=info%3Apmid%2F20947357&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR%3A+a+master+conductor+of+cellular+responses+to+DNA+replication+stress.&rft.issn=0968-0004&rft.date=2011&rft.volume=36&rft.issue=3&rft.spage=133&rft.epage=40&rft.artnum=&rft.au=Flynn+RL&rft.au=Zou+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Flynn RL, & Zou L (2011). ATR: a master conductor of cellular responses to DNA replication stress. <span style="font-style: italic;">Trends in biochemical sciences, 36</span> (3), 133-40 PMID: <a class="Z3988" href="" rev="review" span="" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+genetics&rft_id=info%3Apmid%2F19119425&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=ATR+and+Chk1+suppress+a+caspase-3-dependent+apoptotic+response+following+DNA+replication+stress.&rft.issn=1553-7390&rft.date=2009&rft.volume=5&rft.issue=1&rft.spage=&rft.epage=&rft.artnum=&rft.au=Myers+K&rft.au=Gagou+ME&rft.au=Zuazua-Villar+P&rft.au=Rodriguez+R&rft.au=Meuth+M&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Myers K, Gagou ME, Zuazua-Villar P, Rodriguez R, & Meuth M (2009). ATR and Chk1 suppress a caspase-3-dependent apoptotic response following DNA replication stress. <span style="font-style: italic;">PLoS genetics, 5</span> (1) PMID: </a><a href="http://www.ncbi.nlm.nih.gov/pubmed/19119425" rev="review">19119425</a></span></span><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"> </span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cellular+microbiology&rft_id=info%3Apmid%2F26041433&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+nucleolar+interface+of+RNA+viruses.&rft.issn=1462-5814&rft.date=2015&rft.volume=17&rft.issue=8&rft.spage=1108&rft.epage=20&rft.artnum=&rft.au=Rawlinson+SM&rft.au=Moseley+GW&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Rawlinson SM, & Moseley GW (2015). The nucleolar interface of RNA viruses. <span style="font-style: italic;">Cellular microbiology, 17</span> (8), 1108-20 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26041433" rev="review">26041433</a></span> </span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Frontiers+in+microbiology&rft_id=info%3Apmid%2F26082769&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Nucleocytoplasmic+transport+of+nucleocapsid+proteins+of+enveloped+RNA+viruses.&rft.issn=&rft.date=2015&rft.volume=6&rft.issue=&rft.spage=553&rft.epage=&rft.artnum=&rft.au=Wulan+WN&rft.au=Heydet+D&rft.au=Walker+EJ&rft.au=Gahan+ME&rft.au=Ghildyal+R&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Wulan WN, Heydet D, Walker EJ, Gahan ME, & Ghildyal R (2015). Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA viruses. <span style="font-style: italic;">Frontiers in microbiology, 6</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26082769" rev="review">26082769</a></span> </span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F23677787&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Transmissible+gastroenteritis+virus+infection+induces+cell+apoptosis+via+activation+of+p53+signalling.&rft.issn=0022-1317&rft.date=2013&rft.volume=94&rft.issue=Pt+8&rft.spage=1807&rft.epage=17&rft.artnum=&rft.au=Huang+Y&rft.au=Ding+L&rft.au=Li+Z&rft.au=Dai+M&rft.au=Zhao+X&rft.au=Li+W&rft.au=Du+Q&rft.au=Xu+X&rft.au=Tong+D&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Huang Y, Ding L, Li Z, Dai M, Zhao X, Li W, Du Q, Xu X, & Tong D (2013). Transmissible gastroenteritis virus infection induces cell apoptosis via activation of p53 signalling. <span style="font-style: italic;">The Journal of general virology, 94</span> (Pt 8), 1807-17 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/23677787" rev="review">23677787</a></span> </span></div>
thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-89617136351860263902016-02-21T16:50:00.001-05:002016-02-23T09:24:59.155-05:00Arboviruses and co-infections with bacteria: CHIKV and DENV as examples<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Arboviruses such as Dengue Virus (DENV), Chikungunya
Virus (CHIKV) or Zika Virus (ZIKV) are arthropod borne viruses that are
transmitted to humans via a relatively small number of mosquito species, in
particular <i>Aedes spp</i>. and <i>Culex spp</i>., and only rarely does human-to-human
transmission occur. Humans and other vertebrate animals may serve as a
secondary host and in the absence of human-to-human transmission as a reservoir
host. Indeed, uninfected (female) mosquitoes only become infected following a
blood meal from an infected vertebrae. Following viral infection, the viral
particle then needs to enter epithelial cells of the midgut where viral
replication takes place, followed by the egress of viral particles into
hemocoel and subsequent spread into the salivary glands, thus allowing the
infection of humans and/or animals via an insect bite. Within the insect, both
the salivary gland and the midgut are therefore natural barriers to viral
replication. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to the human gut, the insect gut contains an
abundant bacterial flora that may inhibit or promote viral entry as well as
viral replication, including obligate intracellular symbionts that may prevent
viral replication. In the case of <i>Aedes Agypti</i> experimentally infected
with DENV-serotype 2 (DENV-2), treatment with antibiotics reduces viral titres,
and co-infection of midgut epithelial cells of <i>Ae. aegypti</i> larvae and
adults with DENV-2 or CHIKV and <i>Serrata odoroferia </i>(a gram-negative,
anaerobic, bacteria of the<i> Enterobacteriaceae</i>) increases susceptibility
of <i>Ae.aegypti</i> to DENV-2 and CHIKV in the absence of increased viral
replication suggesting that bacteria can at least facilitate viral entry. In
the case of midgut epithelial cells co-infected with CHIKV and <i>S.odoroferia</i>,
CHIKV has been shown to interact with two mitochondrial proteins, namely Hsp60
and Porin.<o:p></o:p></span></span></div>
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<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Furthermore,<span style="mso-spacerun: yes;">
</span>the co-infection of <i>Ae. aqypti </i>but not <i>Ae. notoscriptus</i><span style="mso-spacerun: yes;"> </span>with both DENV and <i>Wolbachia pipientis </i>decreases
viral replication, although the mechanism is not known. It has been speculated
however that the infection of cells with <i>Wolbachia</i> induces the immune response,
which not only targets bacteria but also DENV and -in A<i>e.albopictus</i>-
derived C6/36 cells also inhibits the replication of DENV and CHIKV as shown by
decreased levels of viral RNA and viral titres.</span><span style="font-family: "helvetica";"><o:p></o:p></span></span></span></div>
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<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><span style="mso-spacerun: yes;"> </span><b>CHIKV
and <i>Wolbachia</i> Hsp60 protein <o:p></o:p></b></span></span></div>
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<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">As discussed before, the infection of mouse embryonic
fibroblast (MEF)<span style="mso-spacerun: yes;"> </span>and HeLa cells with
CHIKV induces the formation of autophagosomes via the ER /UPR and oxidative
stress response which at least at the early stages of the replication cycle
does not induce apoptosis and is required for the formation of viral
replication centres in a p62/SQSTM-1, (human) NDP52 and LC3-C dependent manner.
Since prolonged infection of both human and mouse cells may induce
caspase-dependent apoptosis during later stages of the viral replication cycle
due to a prolonged ER and/or oxidative stress response, it might be possible
however that co-infection of C3/36 cells with <i>Wolbachia</i> may inhibit the
ER stress response and thus prevent the formation of viral RCs. Since the
infection of mosquitoe cells with Wolbachia alters the composition of the host
cells miRNA expression both regulating the expression of cellular miRNAs and by
expressing bacterial miRNAs it might be possible that cellular autophagy is
inhibited via inhibiting the expression of autophagy related genes including
Beclin-1. </span><span style="font-family: "helvetica";"><o:p></o:p></span></span></span></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg_AjagBBRc1dkHt6pACh_6jB3uob-q5AQXuTVleTR42KCCMum7FutTzh-rLcRK0211m5JlgcFD3FMJ84voGySl6pZTg6z_t8qmBzFuyzAZsSVqHCn9-pSE1-QP5aVI8tzy8pBQIbzqCZS6/s1600/Arbovirus+and+Coinfections.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg_AjagBBRc1dkHt6pACh_6jB3uob-q5AQXuTVleTR42KCCMum7FutTzh-rLcRK0211m5JlgcFD3FMJ84voGySl6pZTg6z_t8qmBzFuyzAZsSVqHCn9-pSE1-QP5aVI8tzy8pBQIbzqCZS6/s640/Arbovirus+and+Coinfections.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: CHIKV and the ER stress response<br />
<br /></td></tr>
</tbody></table>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi7Umtjrj1zJ-lu9eATrD4zAj1OORhb5gfHmLznB5VyQY7-q-aOpK79OpzQjHqI28cYVH_f9_vu56yDydmzpM6sGCHBxENc8ay_F8VsmL_91SvQogOwm0mrd234GFS1pEe9MK_raG4eThH4/s1600/Arbovirus+and+Coinfections.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi7Umtjrj1zJ-lu9eATrD4zAj1OORhb5gfHmLznB5VyQY7-q-aOpK79OpzQjHqI28cYVH_f9_vu56yDydmzpM6sGCHBxENc8ay_F8VsmL_91SvQogOwm0mrd234GFS1pEe9MK_raG4eThH4/s640/Arbovirus+and+Coinfections.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: CHIKV proteins that induce the ER stress response, leading to different outcomes</td></tr>
</tbody></table>
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><br /></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span style="font-size: large;"><span lang="EN-US" style="color: black; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;">Interestingly, the treatment of PBMCs but not
lymphocytes derived from both asymptomatic endemic normal and chronic patients
with purified recombinant <i style="mso-bidi-font-style: normal;">Wolbachia</i>
Hsp60 (rWMhsp60) induces caspase-dependent apoptosis, which can be inhibited by
autophagy. Apoptosis is induced by the activation of TLR-4 receptors at the
cell surface and inducing the formation of reactive oxygen species (ROS) in
mitochondria. As a result, mitochondrial membrane potential depolarizes,
cytochrome C is released and subsequently downstream caspases (caspase-3 and
-9) are activated, inducing caspase dependent cell death. In addition, </span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: "Palatino Linotype";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">recent research indicates that ROS also induces a
variant of autophagy termed NETosis (<span style="mso-bidi-font-weight: bold;">Neutrophil
extracellular traps), suggesting that <i style="mso-bidi-font-style: normal;">Wolbachia</i>
and/or rWMHsp60 might induce cell death in the absence of classical apoptotic
markers such as exposure of Phosphatidylserine. Activation of TLR-4 however may
also induce autophagy via TRIF/MyD88 mediated cleavage of the Bcl-2/Beclin-1 complex
and thus contributes to the formation of the phagosomes. Subsequently,
bacterial induced autophagy may induce the cellular antibacterial response as
well as promoting the presentation of antigens via the MHC Class II complex. </span></span><span style="font-family: "helvetica";"><o:p></o:p></span></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiZ6mns9B4vlV5ogXYFZsLIDJq0MtjZ63ITsTOayK40gJ-vJpG5LQslFyB9DrUIkpDcylBXQ5HJuDigidiDB5jIfZDoUpTtNCoq9gpxH7oR98GYKwWpxrmPWw9kXn9_R64QFb3TjWglQ-kM/s1600/Arbovirus+and+Coinfections.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiZ6mns9B4vlV5ogXYFZsLIDJq0MtjZ63ITsTOayK40gJ-vJpG5LQslFyB9DrUIkpDcylBXQ5HJuDigidiDB5jIfZDoUpTtNCoq9gpxH7oR98GYKwWpxrmPWw9kXn9_R64QFb3TjWglQ-kM/s640/Arbovirus+and+Coinfections.003.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Binding of rWMhsp60 to TLR-4 stimulates NETosis and/or caspase dependent apoptosis</td></tr>
</tbody></table>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgiXGwZVu7qFHttrKddiBTZBtBMjfJFWZI9OhzBSGdsVzyBcbtZjTlB8KR-BmK_sToN_nMuRtI5pwyx3NfUAh5lvV_7IwxCxyY6tNefAZVTAUyQdZl5h_lDVg1yydIAtAOCCN6t17XM8C6B/s1600/Arbovirus+and+Coinfections.005.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgiXGwZVu7qFHttrKddiBTZBtBMjfJFWZI9OhzBSGdsVzyBcbtZjTlB8KR-BmK_sToN_nMuRtI5pwyx3NfUAh5lvV_7IwxCxyY6tNefAZVTAUyQdZl5h_lDVg1yydIAtAOCCN6t17XM8C6B/s640/Arbovirus+and+Coinfections.005.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: WMHsp60 might activate TLR-4 induced formation of ROS and thus promotes the degradation<br />
viral RC</td></tr>
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<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Treatment of cells derived from endemic normal but not
chronic patients with Rapamycin and purified rWMhsp60 however induces not only
the formation of autophagosomes but also prevents apoptosis; if autophagic flux
is inhibited has not been demonstrated, although the results suggest that this
is the case since TLR-4 localises inside LC3 positive vesicles. In any case,
these results suggest that C3/36 cells infected with CHIKV may undergo
apoptosis in the presence of <i>Wolbachia</i> or at least if expressing
WMhsp60. Alternatively, <i>Wolbachia</i> derived Hsp60 might sequester CHIKV
viral particles and/or CHIKV viral proteins, thus inhibiting release of the
viral genome, viral assembly, and/or viral egress. Whilst this has not been
investigated yet, it is known that in cells derived from the midgut epithelium
and infected with both CHIKV and <i>Wolbachia</i>, CHIKV binds to Hsp60. Given
that in cells treated rWMhsp60 apoptosis is induced by depolarization of the
mitochondrial membrane, the induction of autophagy by rapamycin might induce
mitophagy; consequently CHIKV (bound to mitochondrial Hsp60) might be degraded
by mitophagy. In addition, the co-infection with CHIKV may promote the
presentation of both viral and bacterial antigens via the MHC Class II complex
and thus promote the induction of the immune response.</span> <span style="font-family: "helvetica";"><o:p></o:p></span></span></span></div>
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<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">It should be noted however that Hsp60 is also located
at the cell surface and rWMhsp60 has been reported to interact with cell
surface TLR-4, leading to the activation of a pro-apoptotic cell signaling
pathway including the induction of oxidative stress signaling and the
activation of caspase-3. The induction of autophagy by Rapamycin relocalises
TLR-4 to late endosomes thus preventing the activation of the pathways.
Analogous to Rapamycin treatment, the induction of the ER stress response by
CHIKV might relocalise TLR-4 in rWMHsp60 treated mosquito cells as well, thus
inhibiting antiviral as well as antibacterial signaling pathways. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The problem is that any effect on the autophagic flux
has not been evaluated and consequently any effect on the stability on the
viral RC is only hypothetic. If autophagic flux however increases in Rapamycin
treated and <i>Wolbachia</i> infected cells, then the co-infection with CHIKV
might induce the degradation of not only TLR-4 (and thus protect cells from <i style="mso-bidi-font-style: normal;">Wolbachia </i>induced apoptosis) but also of
the viral RC (and thus decrease viral replication) particularly at early stages
of viral replication during formation of the RC. <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In conclusion, <i>Wolbachia</i> might either sequester
viral particles and/or viral proteins via WMhsp60 or alternatively CHIKV
induced formation of autophagosomes might facilitate the degradation of TLR-4
and viral RC, thus not only preventing apoptosis (and senescence) but also
leading to reduced viral replication. Additionally, inducing the degradation of
viral RCs and/or TLR-4 following the infection of Wolbachia containing cells
might also degrade Wolbachia itself since the induction of autophagy has also
been shown to degrade <i>Wolbachia </i>in C3/36 and PC35 cells. <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<b><span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">DENV and <i>Wolbachia</i>: inhibition of viral entry
v. protection of WMHsp60 induced apoptosis<o:p></o:p></span></span></b></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">In the case of DENV, the viral NS1 protein has been
reported to localize to vesicular structures containing the viral NS5, NS3,
NS2A, NS2B, NS4A and NS1 proteins as well as dsRNA and the viral RNA dependent
RNA Polymerase (RdRP) in infected Vero and C6/36 cells. In subsequent studies,
it was shown that the formation of viral RC -similar to other positive strand
viruses such as Poliovirus and Coronaviruses- is dependent on autophagy as
evidenced by decreased viral replication in autophagy deficient MEF cells,
knockdown of autophagy related genes, or treatment with 3-Methyladenine (3-MA)
of DENV-2 or DENV-3 infected human Pre-Basophils/Mast KU812, Huh7 and HepG2
cells as well as increased viral replication in DENV-3 infected HepG2 cells
treated with Rapamycin. DENV RC however do not represent classical
autophagosomes but rather invaginations of ER cisternae that may mature into
amphisomes as a result of the fusion of endosomes with autophagosomes as
indicated by the co-localization of dsRNA with mannose-6-phosphate receptor
(MPR) as well as LC3. In addition, DENV inhibits Torin-1 induced, starvation
induced and basal autophagic flux in Huh7 cells as evidenced by the use of a
mCherry-LC3 reporter plasmid whilst inducing the proteasomal degradation of p62/SQSTM-1,
suggesting that the formation of viral RC indeed might be not entirely
dependent on autophagy related proteins. The induction of autophagy by DENV
however is required for the degradation of lipid droplets and the release of
lipids thus stimulating lipid metabolism via selective autophagy.</span><span style="font-family: "helvetica";"><o:p></o:p></span></span></span></div>
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<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><br /></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><br /></span></span></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhuRC0MyKaE8Asb8FAF8yqI9ypu6G3F5WcYiNwfVEbCPYh1-RX108jFOl4Rna0iP5mqe1ip8BF4kll7tFR_2le0swPPSHy-9LOx0DeHnyXZo__vwf-VXwbbDNT1KuAMUfRNHS9bhsa9a0mX/s1600/Arbovirus+and+Coinfections.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhuRC0MyKaE8Asb8FAF8yqI9ypu6G3F5WcYiNwfVEbCPYh1-RX108jFOl4Rna0iP5mqe1ip8BF4kll7tFR_2le0swPPSHy-9LOx0DeHnyXZo__vwf-VXwbbDNT1KuAMUfRNHS9bhsa9a0mX/s640/Arbovirus+and+Coinfections.006.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: DENV induction of lipophagy - connection to mitophay?</td></tr>
</tbody></table>
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<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><br /></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to other viruses, DENV therefore has been
postulated to induce the formation of autophagosome or autophagosome-like
structures early in the replication cycle whilst inhibiting autophagic flux
later in the replication cycle. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In the case of mosquito cells, C3/36 cells infected
with DENV support the findings obtained from mammalian cells is so far as the
viral RC are in close proximity to the ER and coated with ribosomes (similar to
the co-localization of dsRNA with L28 in DENV-2 infected HepG2 cells)<span style="mso-spacerun: yes;"> </span>and similar to mammalian cells, cellular
fatty acid synthase is redistributed to the viral RC (by the viral NS3 protein
and dependent on Rab18). <o:p></o:p></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The degradation of lipid droplets by DENV induced
autophagy might therefore be conserved in both mammalian and mosquito cells. In
the case of mosquito cells infected with both <i>Wolbachia</i> and DENV
however, DENV might prevent cells from WMhsp60 induced apoptosis and senescence
by either sequestering TLR-4 in amphisomes and/or degradation of TLR-4 at least
early in infection whereas later in infection due to the inhibition of
autophagic flux TLR-4 might accumulate in late endosomes or amphisomes. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">However, this might only apply if the infection of
cells with DENV occurs prior the infection with <i>Wolbachia</i> since <i>Wolbachia</i>
has been reported to prevent the entry of DENV and other Flavivirus' into cells
by sequestering cholesterol. In contrast, <i>Serratia</i> <i>odorifera</i>
might increase viral entry by increasing prohibitin on the cell surface.
Mitochondria localized prohibitin has also been shown to inhibit mitophagy, but
in the absence of data it is not possible to discern if <i>Serratia</i> <i>odorifera</i>
induces merely the redistribution of either HSP60 and/or Prohibitin or
alternatively promotes the redistribution of mitochondria to sites of viral
replication. The pore forming ShlA toxin from <i>Serratia marcesens </i>has
been shown to induce autophagy in CHO cells, a potential homologoue in <i>Serratia</i>
<i>odorifera </i>might increase DENV replication by facilitating the fusion of
lipid droplets with autophagosomes and lysosomes.<o:p></o:p></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<b><span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="mso-spacerun: yes;"> </span>Lipophagy:
autophagy of lipid droplets<o:p></o:p></span></span></b></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Autophagy has been shown to regulate the metabolism of
lipid droplets that are storage areas of triglycerides (TG) and cholesterol
both in the absence and presence of viral replication. The induction of
autophagy correlates with the decrease of triglyceride levels since the fusion
of lipid droplets (LD) with autophagosomes and subsequent lysosomal fusion induces
the release of free fatty acids in a process commonly referred to as lipophagy
which requires both lipases and the small Rab7GTPase. Free fatty acids released
by lipophagy generate ATP by mitochondrial β-oxidation and thus contribute<span style="mso-spacerun: yes;"> </span>to the maintenance of<span style="mso-spacerun: yes;"> </span>the cellular energy homeostasis. In the
context of viral replication, Brome Mosaic Virus replication is dependent on
specific localised lipid compositions whereas West Nile Virus induces the
synthesis and redistribution of cholesterol to sites of viral replication. In
the case of Hepatitis C Virus (HCV) -arguably the most prominent virus that
utilises lipid droplets for viral replication- assembly of viral particles
takes place at lipid droplets and the release of viral particles is dependent
on the very low-density lipid secretion pathway. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Inf DENV-2 infected Huh 7.5 cells, the induction of
autophagy not only protects cells from apoptosis induced by the UPR pathway but
also decreases TG levels and LD area by approx. 35% (leading to a reduction of
approx. 70% of the LD volume) as measured by oil red staining and EM
respectively at 48 hrs p.i. .Treatment of infected cells with either 3-MA or
transfection with siRNA targeting Beclin-1 or ATG12 prior infection results in
a marked increase in LD compared to mock treated cells, indicating that indeed
not only the induction of autophagy is necessary for DENV-2 induced lipophagy.
Accordingly, lipophagy should be inhibited at later stages of the replication
cycle. Rather than inducing the formation of autophagosomes however, DENV-2
might rather promote the fusion of autophagosomes with LD as indicated by
results showing that the number of lysosomes is not altered in DENV-2 infected
Huh 7.5 cells but that the number of structures positive for both Bodipy 493/503
and Lysotracker increases.<span style="mso-spacerun: yes;"> </span>Using a novel
inhibitor, SAR-405, which targets the Vps34 kinase should clarify if DENV-2
does induce the formation of mitophagosomes akin to HCV or alternatively
promotes the fusion of existing autophagosomes independent of <i>de novo</i>
formed mitophagosomes. So far however DENV NS4A has not been shown to exhibit
mitochondrial localisation in infected Huh 7 cells. The free fatty acids
generated by the degradation of TG however are not utilised to generate ATP but
also required for the formation of viral particles; free fatty acids are
recruited to viral RC via an interaction between the viral DENV NS3 protein
localised at the ER and free fatty acids in a Rab18GTPase dependent manner. In
addition to mitophagy, lipid droplets may also be degraded by autophagy.</span><span style="font-family: "helvetica";"><o:p></o:p></span></span></span></div>
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<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhKXlskKhhw5tNTUaD3Hrteag13wqRYiaR72rmYkCz0dcjCe8j1NitRN4bvrDKGgFYsvUbaS3tmu9HXPCzCvgAW-DVfBLX7waRJNCS2cuV3VQHHIouU1CDhEtWwJuimlshUJI5ApXv0K1-t/s1600/Arbovirus+and+Coinfections.007.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhKXlskKhhw5tNTUaD3Hrteag13wqRYiaR72rmYkCz0dcjCe8j1NitRN4bvrDKGgFYsvUbaS3tmu9HXPCzCvgAW-DVfBLX7waRJNCS2cuV3VQHHIouU1CDhEtWwJuimlshUJI5ApXv0K1-t/s640/Arbovirus+and+Coinfections.007.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: DENV and ZIKV induce autophagy and/or mitophagy and lipophagy</td></tr>
</tbody></table>
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<span style="font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Recent evidence however suggests that in Aag-2 cells derived from Aedes Aqypti, </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">both</span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> the infection with bacteria and with Sindbis Virus (SINV) or DENV increases the number of LD, suggesting that the induction of LD synthesis induces the antiviral and antibacterial response. It should be noted however that the authors did not evaluate lipophagy and/or the co-localisation of LD with LC3 in these cells. </span></span><br />
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<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to Vero cells transfected with the
Polyomavirus BK Angnoprotein or Polyomavirus BK infected cells, LD in DENV-2
infected cells are localised in close proximity to the ER, which is in
accordance with the site of viral replication, but similar to DENV, an
accumulation of mitoplysophagsomes has not been demonstrated for Polyomavirus.
.<o:p></o:p></span></span></div>
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<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
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<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In the case of co-infection of cells with DENV-2 and <i>Serratia
odorifera</i>,<i><span style="mso-spacerun: yes;"> </span></i>mitochondria might<i>
</i><span style="mso-spacerun: yes;"> </span>relocated to the site of viral
replication and thus increase the availability of ATP provided if the bacterial
HSP60 and/or Prohibitin localises to the mitochondria of the host cell and
interacts with viral proteins localised at the ER. If these mitochondria are
susceptible to depolarisation and undergo mitophagy remains also to be seen.<o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><br /></span></div>
<div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Helvetica;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Finally in my opinion, DENV might increase replication
of ZIKV by increasing the turnover of LD, thus providing a favourable
environment for ZIKV replication.\<o:p></o:p></span></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In summary, both <i>Wolbachia</i> and <i>Serratia</i> <i>odorifera </i>might play an important role in regulating the replication of CHIKV, DENV, and potentially ZIKV in mosquito cells both by decreasing and increasing viral titres. Further research is however need to establish the nature of these interactions.</span><br />
<span style="float: left; padding: 5px;"><a href="http://www.researchblogging.org/"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_gray.png" style="border: 0;" /></a></span>
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<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26872460&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Arboviruses+and+apoptosis%3A+the+role+of+cell+death+in+determining+vector+competence.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26872460&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Arboviruses+and+apoptosis%3A+the+role+of+cell+death+in+determining+vector+competence.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><b><u><br /></u></b></span><br />
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26872460&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Arboviruses+and+apoptosis%3A+the+role+of+cell+death+in+determining+vector+competence.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><b><u><br /></u></b></span>
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26872460&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Arboviruses+and+apoptosis%3A+the+role+of+cell+death+in+determining+vector+competence.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><b><u><br /></u></b></span>
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26872460&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Arboviruses+and+apoptosis%3A+the+role+of+cell+death+in+determining+vector+competence.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><b><u>Further reading</u></b></span><br />
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26872460&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Arboviruses+and+apoptosis%3A+the+role+of+cell+death+in+determining+vector+competence.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26872460&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Arboviruses+and+apoptosis%3A+the+role+of+cell+death+in+determining+vector+competence.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Clem RJ (2016). Arboviruses and apoptosis: the role of cell death in determining vector competence. <span style="font-style: italic;">The Journal of general virology</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26872460" rev="review">26872460</a></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26872460&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Arboviruses+and+apoptosis%3A+the+role+of+cell+death+in+determining+vector+competence.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F26872460&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Arboviruses+and+apoptosis%3A+the+role+of+cell+death+in+determining+vector+competence.&rft.issn=0022-1317&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Viruses&rft_id=info%3Apmid%2F26184281&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Tissue+Barriers+to+Arbovirus+Infection+in+Mosquitoes.&rft.issn=&rft.date=2015&rft.volume=7&rft.issue=7&rft.spage=3741&rft.epage=67&rft.artnum=&rft.au=Franz+AW&rft.au=Kantor+AM&rft.au=Passarelli+AL&rft.au=Clem+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Franz AW, Kantor AM, Passarelli AL, & Clem RJ (2015). Tissue Barriers to Arbovirus Infection in Mosquitoes. <span style="font-style: italic;">Viruses, 7</span> (7), 3741-67 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26184281" rev="review">26184281</a></span>
</span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Current+opinion+in+virology&rft_id=info%3Apmid%2F26363996&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+microbiome+modulates+arbovirus+transmission+in+mosquitoes.&rft.issn=1879-6257&rft.date=2015&rft.volume=15&rft.issue=&rft.spage=97&rft.epage=102&rft.artnum=&rft.au=Hegde+S&rft.au=Rasgon+JL&rft.au=Hughes+GL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Hegde S, Rasgon JL, & Hughes GL (2015). The microbiome modulates arbovirus transmission in mosquitoes. <span style="font-style: italic;">Current opinion in virology, 15</span>, 97-102 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26363996" rev="review">26363996</a></span> </span><br />
<br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Viruses&rft_id=info%3Apmid%2F25393895&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+insect+microbiome+modulates+vector+competence+for+arboviruses.&rft.issn=&rft.date=2014&rft.volume=6&rft.issue=11&rft.spage=4294&rft.epage=313&rft.artnum=&rft.au=Jupatanakul+N&rft.au=Sim+S&rft.au=Dimopoulos+G&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Jupatanakul N, Sim S, & Dimopoulos G (2014). The insect microbiome modulates vector competence for arboviruses. <span style="font-style: italic;">Viruses, 6</span> (11), 4294-313 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25393895" rev="review">25393895</a></span> </span><br />
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Apoptosis+%3A+an+international+journal+on+programmed+cell+death&rft_id=info%3Apmid%2F16820968&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Apoptosis+in+mosquito+midgut+epithelia+associated+with+West+Nile+virus+infection.&rft.issn=1360-8185&rft.date=2006&rft.volume=11&rft.issue=9&rft.spage=1643&rft.epage=51&rft.artnum=&rft.au=Vaidyanathan+R&rft.au=Scott+TW&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Apoptosis+%3A+an+international+journal+on+programmed+cell+death&rft_id=info%3Apmid%2F16820968&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Apoptosis+in+mosquito+midgut+epithelia+associated+with+West+Nile+virus+infection.&rft.issn=1360-8185&rft.date=2006&rft.volume=11&rft.issue=9&rft.spage=1643&rft.epage=51&rft.artnum=&rft.au=Vaidyanathan+R&rft.au=Scott+TW&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Vaidyanathan R, & Scott TW (2006). Apoptosis in mosquito midgut epithelia associated with West Nile virus infection. <span style="font-style: italic;">Apoptosis : an international journal on programmed cell death, 11</span> (9), 1643-51 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/16820968" rev="review">16820968</a></span> </span><br />
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F2896802&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Togavirus-associated+pathologic+changes+in+the+midgut+of+a+natural+mosquito+vector.&rft.issn=0022-538X&rft.date=1988&rft.volume=62&rft.issue=6&rft.spage=2083&rft.epage=90&rft.artnum=&rft.au=Weaver+SC&rft.au=Scott+TW&rft.au=Lorenz+LH&rft.au=Lerdthusnee+K&rft.au=Romoser+WS&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Weaver SC, Scott TW, Lorenz LH, Lerdthusnee K, & Romoser WS (1988). Togavirus-associated pathologic changes in the midgut of a natural mosquito vector. <span style="font-style: italic;">Journal of virology, 62</span> (6), 2083-90 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/2896802" rev="review">2896802</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Viruses&rft_id=info%3Apmid%2F25421891&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Chikungunya+virus-vector+interactions.&rft.issn=&rft.date=2014&rft.volume=6&rft.issue=11&rft.spage=4628&rft.epage=63&rft.artnum=&rft.au=Coffey+LL&rft.au=Failloux+AB&rft.au=Weaver+SC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Coffey LL, Failloux AB, & Weaver SC (2014). Chikungunya virus-vector interactions. <span style="font-style: italic;">Viruses, 6</span> (11), 4628-63 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25421891" rev="review">25421891</a></span> </span><br />
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Indian+journal+of+medical+research&rft_id=info%3Apmid%2F25027087&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Serratia+odorifera+mediated+enhancement+in+susceptibility+of+Aedes+aegypti+for+chikungunya+virus.&rft.issn=0971-5916&rft.date=2014&rft.volume=139&rft.issue=5&rft.spage=762&rft.epage=8&rft.artnum=&rft.au=Apte-Deshpande+AD&rft.au=Paingankar+MS&rft.au=Gokhale+MD&rft.au=Deobagkar+DN&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cell+death+and+differentiation&rft_id=info%3Apmid%2F19444282&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Toll-like+receptors+in+control+of+immunological+autophagy.&rft.issn=1350-9047&rft.date=2009&rft.volume=16&rft.issue=7&rft.spage=976&rft.epage=83&rft.artnum=&rft.au=Delgado+MA&rft.au=Deretic+V&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Delgado MA, & Deretic V (2009). Toll-like receptors in control of immunological autophagy. <span style="font-style: italic;">Cell death and differentiation, 16</span> (7), 976-83 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/19444282" rev="review">19444282</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Biomolecules&rft_id=info%3Apmid%2F25946076&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+Role+of+Reactive+Oxygen+Species+%28ROS%29+in+the+Formation+of+Extracellular+Traps+%28ETs%29+in+Humans.&rft.issn=&rft.date=2015&rft.volume=5&rft.issue=2&rft.spage=702&rft.epage=23&rft.artnum=&rft.au=Stoiber+W&rft.au=Obermayer+A&rft.au=Steinbacher+P&rft.au=Krautgartner+WD&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Stoiber W, Obermayer A, Steinbacher P, & Krautgartner WD (2015). The Role of Reactive Oxygen Species (ROS) in the Formation of Extracellular Traps (ETs) in Humans. <span style="font-style: italic;">Biomolecules, 5</span> (2), 702-23 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25946076" rev="review">25946076</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=World+journal+of+gastroenterology&rft_id=info%3Apmid%2F24627598&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Hepatitis+C+virus%2C+mitochondria+and+auto%2Fmitophagy%3A+exploiting+a+host+defense+mechanism.&rft.issn=1007-9327&rft.date=2014&rft.volume=20&rft.issue=10&rft.spage=2624&rft.epage=33&rft.artnum=&rft.au=Ruggieri+V&rft.au=Mazzoccoli+C&rft.au=Pazienza+V&rft.au=Andriulli+A&rft.au=Capitanio+N&rft.au=Piccoli+C&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Ruggieri V, Mazzoccoli C, Pazienza V, Andriulli A, Capitanio N, & Piccoli C (2014). Hepatitis C virus, mitochondria and auto/mitophagy: exploiting a host defense mechanism. <span style="font-style: italic;">World journal of gastroenterology, 20</span> (10), 2624-33 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24627598" rev="review">24627598</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Virology&rft_id=info%3Apmid%2F20138326&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+polyomavirus+BK+agnoprotein+co-localizes+with+lipid+droplets.&rft.issn=0042-6822&rft.date=2010&rft.volume=399&rft.issue=2&rft.spage=322&rft.epage=31&rft.artnum=&rft.au=Unterstab+G&rft.au=Gosert+R&rft.au=Leuenberger+D&rft.au=Lorentz+P&rft.au=Rinaldo+CH&rft.au=Hirsch+HH&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Unterstab G, Gosert R, Leuenberger D, Lorentz P, Rinaldo CH, & Hirsch HH (2010). The polyomavirus BK agnoprotein co-localizes with lipid droplets. <span style="font-style: italic;">Virology, 399</span> (2), 322-31 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20138326" rev="review">20138326</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Hepatology+%28Baltimore%2C+Md.%29&rft_id=info%3Apmid%2F25565581&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+small+GTPase+Rab7+as+a+central+regulator+of+hepatocellular+lipophagy.&rft.issn=0270-9139&rft.date=2015&rft.volume=61&rft.issue=6&rft.spage=1896&rft.epage=907&rft.artnum=&rft.au=Schroeder+B&rft.au=Schulze+RJ&rft.au=Weller+SG&rft.au=Sletten+AC&rft.au=Casey+CA&rft.au=McNiven+MA&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Schroeder B, Schulze RJ, Weller SG, Sletten AC, Casey CA, & McNiven MA (2015). The small GTPase Rab7 as a central regulator of hepatocellular lipophagy. <span style="font-style: italic;">Hepatology (Baltimore, Md.), 61</span> (6), 1896-907 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25565581" rev="review">25565581</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F26018155&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dengue+Virus+Inhibition+of+Autophagic+Flux+and+Dependency+of+Viral+Replication+on+Proteasomal+Degradation+of+the+Autophagy+Receptor+p62.&rft.issn=0022-538X&rft.date=2015&rft.volume=89&rft.issue=15&rft.spage=8026&rft.epage=41&rft.artnum=&rft.au=Metz+P&rft.au=Chiramel+A&rft.au=Chatel-Chaix+L&rft.au=Alvisi+G&rft.au=Bankhead+P&rft.au=Mora-Rodriguez+R&rft.au=Long+G&rft.au=Hamacher-Brady+A&rft.au=Brady+NR&rft.au=Bartenschlager+R&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Metz P, Chiramel A, Chatel-Chaix L, Alvisi G, Bankhead P, Mora-Rodriguez R, Long G, Hamacher-Brady A, Brady NR, & Bartenschlager R (2015). Dengue Virus Inhibition of Autophagic Flux and Dependency of Viral Replication on Proteasomal Degradation of the Autophagy Receptor p62. <span style="font-style: italic;">Journal of virology, 89</span> (15), 8026-41 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26018155" rev="review">26018155</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Infection+and+immunity&rft_id=info%3Apmid%2F24914224&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Serratia+marcescens+ShlA+pore-forming+toxin+is+responsible+for+early+induction+of+autophagy+in+host+cells+and+is+transcriptionally+regulated+by+RcsB.&rft.issn=0019-9567&rft.date=2014&rft.volume=82&rft.issue=9&rft.spage=3542&rft.epage=54&rft.artnum=&rft.au=Di+Venanzio+G&rft.au=Stepanenko+TM&rft.au=Garc%C3%ADa+V%C3%A9scovi+E&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Di Venanzio G, Stepanenko TM, & García Véscovi E (2014). Serratia marcescens ShlA pore-forming toxin is responsible for early induction of autophagy in host cells and is transcriptionally regulated by RcsB. <span style="font-style: italic;">Infection and immunity, 82</span> (9), 3542-54 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24914224" rev="review">24914224</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Virology&rft_id=info%3Apmid%2F20674955&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Identification+and+characterization+of+prohibitin+as+a+receptor+protein+mediating+DENV-2+entry+into+insect+cells.&rft.issn=0042-6822&rft.date=2010&rft.volume=406&rft.issue=1&rft.spage=149&rft.epage=61&rft.artnum=&rft.au=Kuadkitkan+A&rft.au=Wikan+N&rft.au=Fongsaran+C&rft.au=Smith+DR&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Kuadkitkan A, Wikan N, Fongsaran C, & Smith DR (2010). Identification and characterization of prohibitin as a receptor protein mediating DENV-2 entry into insect cells. <span style="font-style: italic;">Virology, 406</span> (1), 149-61 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20674955" rev="review">20674955</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Applied+and+environmental+microbiology&rft_id=info%3Apmid%2F26407882&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Wolbachia-mediated+antiviral+protection+in+Drosophila+larvae+and+adults+following+oral+infection.&rft.issn=0099-2240&rft.date=2015&rft.volume=81&rft.issue=23&rft.spage=8215&rft.epage=23&rft.artnum=&rft.au=Stevanovic+AL&rft.au=Arnold+PA&rft.au=Johnson+KN&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Stevanovic AL, Arnold PA, & Johnson KN (2015). Wolbachia-mediated antiviral protection in Drosophila larvae and adults following oral infection. <span style="font-style: italic;">Applied and environmental microbiology, 81</span> (23), 8215-23 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26407882" rev="review">26407882</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> <span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F24696471&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Rab18+facilitates+dengue+virus+infection+by+targeting+fatty+acid+synthase+to+sites+of+viral+replication.&rft.issn=0022-538X&rft.date=2014&rft.volume=88&rft.issue=12&rft.spage=6793&rft.epage=804&rft.artnum=&rft.au=Tang+WC&rft.au=Lin+RJ&rft.au=Liao+CL&rft.au=Lin+YL&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Tang WC, Lin RJ, Liao CL, & Lin YL (2014). Rab18 facilitates dengue virus infection by targeting fatty acid synthase to sites of viral replication. <span style="font-style: italic;">Journal of virology, 88</span> (12), 6793-804 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24696471" rev="review">24696471</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"> <span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America&rft_id=info%3Apmid%2F20855599&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dengue+virus+nonstructural+protein+3+redistributes+fatty+acid+synthase+to+sites+of+viral+replication+and+increases+cellular+fatty+acid+synthesis.&rft.issn=0027-8424&rft.date=2010&rft.volume=107&rft.issue=40&rft.spage=17345&rft.epage=50&rft.artnum=&rft.au=Heaton+NS&rft.au=Perera+R&rft.au=Berger+KL&rft.au=Khadka+S&rft.au=Lacount+DJ&rft.au=Kuhn+RJ&rft.au=Randall+G&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Heaton NS, Perera R, Berger KL, Khadka S, Lacount DJ, Kuhn RJ, & Randall G (2010). Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. <span style="font-style: italic;">Proceedings of the National Academy of Sciences of the United States of America, 107</span> (40), 17345-50 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/20855599" rev="review">20855599</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F24522909&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ultrastructural+characterization+and+three-dimensional+architecture+of+replication+sites+in+dengue+virus-infected+mosquito+cells.&rft.issn=0022-538X&rft.date=2014&rft.volume=88&rft.issue=9&rft.spage=4687&rft.epage=97&rft.artnum=&rft.au=Junjhon+J&rft.au=Pennington+JG&rft.au=Edwards+TJ&rft.au=Perera+R&rft.au=Lanman+J&rft.au=Kuhn+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Junjhon J, Pennington JG, Edwards TJ, Perera R, Lanman J, & Kuhn RJ (2014). Ultrastructural characterization and three-dimensional architecture of replication sites in dengue virus-infected mosquito cells. <span style="font-style: italic;">Journal of virology, 88</span> (9), 4687-97 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24522909" rev="review">24522909</a></span> </span><br />
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Annual+Review+of+Virology&rft_id=info%3Adoi%2F10.1146%2Fannurev-virology-100114-055007&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Flaviviridae+Replication+Organelles%3A+Oh%2C+What+a+Tangled+Web+We+Weave&rft.issn=2327-056X&rft.date=2015&rft.volume=2&rft.issue=1&rft.spage=289&rft.epage=310&rft.artnum=http%3A%2F%2Fwww.annualreviews.org%2Fdoi%2F10.1146%2Fannurev-virology-100114-055007&rft.au=Paul%2C+D.&rft.au=Bartenschlager%2C+R.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Annual+Review+of+Virology&rft_id=info%3Adoi%2F10.1146%2Fannurev-virology-100114-055007&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Flaviviridae+Replication+Organelles%3A+Oh%2C+What+a+Tangled+Web+We+Weave&rft.issn=2327-056X&rft.date=2015&rft.volume=2&rft.issue=1&rft.spage=289&rft.epage=310&rft.artnum=http%3A%2F%2Fwww.annualreviews.org%2Fdoi%2F10.1146%2Fannurev-virology-100114-055007&rft.au=Paul%2C+D.&rft.au=Bartenschlager%2C+R.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Paul, D., & Bartenschlager, R. (2015). Flaviviridae Replication Organelles: Oh, What a Tangled Web We Weave <span style="font-style: italic;">Annual Review of Virology, 2</span> (1), 289-310 DOI: <a href="http://dx.doi.org/10.1146/annurev-virology-100114-055007" rev="review">10.1146/annurev-virology-100114-055007</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=PLoS+pathogens&rft_id=info%3Apmid%2F22457619&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dengue+virus+infection+perturbs+lipid+homeostasis+in+infected+mosquito+cells.&rft.issn=1553-7366&rft.date=2012&rft.volume=8&rft.issue=3&rft.spage=&rft.epage=&rft.artnum=&rft.au=Perera+R&rft.au=Riley+C&rft.au=Isaac+G&rft.au=Hopf-Jannasch+AS&rft.au=Moore+RJ&rft.au=Weitz+KW&rft.au=Pasa-Tolic+L&rft.au=Metz+TO&rft.au=Adamec+J&rft.au=Kuhn+RJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Perera R, Riley C, Isaac G, Hopf-Jannasch AS, Moore RJ, Weitz KW, Pasa-Tolic L, Metz TO, Adamec J, & Kuhn RJ (2012). Dengue virus infection perturbs lipid homeostasis in infected mosquito cells. <span style="font-style: italic;">PLoS pathogens, 8</span> (3) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/22457619" rev="review">22457619</a></span> </span><br />
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F19141455&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Co-localization+of+constituents+of+the+dengue+virus+translation+and+replication+machinery+with+amphisomes.&rft.issn=0022-1317&rft.date=2009&rft.volume=90&rft.issue=Pt+2&rft.spage=448&rft.epage=56&rft.artnum=&rft.au=Panyasrivanit+M&rft.au=Khakpoor+A&rft.au=Wikan+N&rft.au=Smith+DR&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Panyasrivanit M, Khakpoor A, Wikan N, & Smith DR (2009). Co-localization of constituents of the dengue virus translation and replication machinery with amphisomes. <span style="font-style: italic;">The Journal of general virology, 90</span> (Pt 2), 448-56 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/19141455" rev="review">19141455</a></span> </span><br />
<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Molecular+and+cellular+biochemistry&rft_id=info%3Apmid%2F25138703&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Coordinated+regulation+of+autophagy+and+apoptosis+determines+endothelial+cell+fate+during+Dengue+virus+type+2+infection.&rft.issn=0300-8177&rft.date=2014&rft.volume=397&rft.issue=1-2&rft.spage=157&rft.epage=65&rft.artnum=&rft.au=Huang+J&rft.au=Li+Y&rft.au=Qi+Y&rft.au=Zhang+Y&rft.au=Zhang+L&rft.au=Wang+Z&rft.au=Zhang+X&rft.au=Gui+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span>
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Molecular+and+cellular+biochemistry&rft_id=info%3Apmid%2F25138703&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Coordinated+regulation+of+autophagy+and+apoptosis+determines+endothelial+cell+fate+during+Dengue+virus+type+2+infection.&rft.issn=0300-8177&rft.date=2014&rft.volume=397&rft.issue=1-2&rft.spage=157&rft.epage=65&rft.artnum=&rft.au=Huang+J&rft.au=Li+Y&rft.au=Qi+Y&rft.au=Zhang+Y&rft.au=Zhang+L&rft.au=Wang+Z&rft.au=Zhang+X&rft.au=Gui+L&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Huang J, Li Y, Qi Y, Zhang Y, Zhang L, Wang Z, Zhang X, & Gui L (2014). Coordinated regulation of autophagy and apoptosis determines endothelial cell fate during Dengue virus type 2 infection. <span style="font-style: italic;">Molecular and cellular biochemistry, 397</span> (1-2), 157-65 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25138703" rev="review">25138703</a></span> </span><br />
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Biomedical+Science&rft_id=info%3Adoi%2F10.1186%2F1423-0127-20-65&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Dengue+virus+infection+induces+autophagy%3A+an+in+vivo+study&rft.issn=1423-0127&rft.date=2013&rft.volume=20&rft.issue=1&rft.spage=65&rft.epage=&rft.artnum=http%3A%2F%2Fwww.jbiomedsci.com%2Fcontent%2F20%2F1%2F65&rft.au=Lee%2C+Y.&rft.au=Hu%2C+H.&rft.au=Kuo%2C+S.&rft.au=Lei%2C+H.&rft.au=Lin%2C+Y.&rft.au=Yeh%2C+T.&rft.au=Liu%2C+C.&rft.au=Liu%2C+H.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Lee, Y., Hu, H., Kuo, S., Lei, H., Lin, Y., Yeh, T., Liu, C., & Liu, H. (2013). Dengue virus infection induces autophagy: an in vivo study <span style="font-style: italic;">Journal of Biomedical Science, 20</span> (1) DOI: <a href="http://dx.doi.org/10.1186/1423-0127-20-65" rev="review">10.1186/1423-0127-20-65</a></span><br />
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Ana Beatriz Ferreira Barletta, Liliane Rosa Alves, Maria Clara L. Nascimento Silva, Shuzhen Sim, George Dimopoulos, Sally Liechocki, Clarissa M. Maya-Monteiro & Marcos H. Ferreira Sorgine</span><br />
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Emerging role of lipid droplets in Aedes aegypti immune response against bacteria and Dengue virus</span><br />
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Scientific Reports 6:19928</span><br />
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-32699252312280515392016-02-06T14:57:00.003-05:002016-02-06T15:01:02.722-05:00Zika Virus, Microcephaly and Brazil<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><a href="http://virologytidbits.blogspot.com/2016/01/zika-virus-zikv-similarities-to-other.html" target="_blank">As discussed before</a>, Zika Virus (ZIKV) is an
emerging arbovirus, spread by Aedes <i>Agypti
</i>and <i>Aedes albopictus</i>, which was
first isolated in 1947 in Uganda from a Macaca monkey with the first human case
being detected in Nigeria (1954). In subsequent decades sporadic cases linked
to ZIKV have been reported in Africa and Asia, with a first epidemic reported
in 2008 (Yap/Federated States of Micronesia) and a larger one in French
Polynesia and Oceania 2013-2014 with the first cases in the Americas were
identified in Natal/Brazil in March 2015 in samples from patients displaying
dengue-like symptoms. </span><span style="font-family: "helvetica";"><o:p></o:p></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjKywZgDwRx3tNJXMAtH4u0P_rgyCU3EJqr0QdBMWaX2n7DyoooWY_Y_H94IIL_rLevKDsv6inHPhhWn0fo6IAEZE9S2zOT9F-cW9mDQ-7wgv32-eEI3HKu7J00LZ4EAuTfoEBPnUY4-cOg/s1600/Zika+blog.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjKywZgDwRx3tNJXMAtH4u0P_rgyCU3EJqr0QdBMWaX2n7DyoooWY_Y_H94IIL_rLevKDsv6inHPhhWn0fo6IAEZE9S2zOT9F-cW9mDQ-7wgv32-eEI3HKu7J00LZ4EAuTfoEBPnUY4-cOg/s400/Zika+blog.001.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table1: Outbreaks of ZIKV 1952-2014</td></tr>
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<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Although most patients experience only a fever or
a rash –or even are asymptomatic- following ZIKV infection, during the outbreak
in French Polynesia an increase in patients suffering from an otherwise rare
neurological disorder, Guillan-Barre Syndrome (GBS), has been reported and
associated with a previous ZIKV infection, suggesting that ZIKV might be a
neurotropic virus (similar to DENGV or CHIKV), a view supported by studies that
suggest that ZIKV can infect and replicate in neuronal cells. If however the
infection of ZIKV with neuronal cells is causing GBS has not been established
and it might be possible that the immune response –rather than the infection
per se- causes the neurological abnormalities reported during the 2013-2014
outbreak.</span></span></div>
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<span style="font-family: "helvetica";"><span style="font-size: large;"><span style="mso-spacerun: yes;"><span style="font-family: "helvetica";"> </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"> </span></span><b><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">ZIKV in Brazil</span></b><span style="font-family: "helvetica";"><o:p></o:p></span></span></span></div>
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<span style="font-family: "helvetica";"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The transmission of ZIKV from the Pacific Islands
to Brazil appears to have happened either during the 2014 FIFA World Cup and/or
an international canoe-racing event attended exclusively by competitors from
the Pacific. Although the first ZIKV were isolated from patients in the city of
Natal, patients with symptoms suggesting ZIKV infection were reported in the
city of San Salvador from February 15 onwards, and ever since a total of 28
Brazilian states have reported cases of Zika (as of February 06 2016). Following
the detection of ZIKV in Brazil, confirmed cases have been reported in
throughout Central and South America (with the exception being Chile) as well
as the Caribbean.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></span></div>
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<span style="font-family: "helvetica";"><span style="font-size: large;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;">Travellers to these countries also lead to the
appearance of confirmed cases in Europe, the Near East, Australia, and the US.
With the exception of the US, so far however no local transmission has been
reported in these countries. In the US, the only cases of transmission occurred
horizontally by sexual intercourse and not via mosquitoes. Given the ubiquitous
presence of the vector, it is expected that ZIKV being locally transmitted not
only in Central and South America (with the exception of Chile) as well as the
Caribbean but also in the southern part of the US with expected number of both
symptomatic and asymptomatic cases of 3-4 million for 2016 (based on
mathematical models). </span><span style="font-family: "helvetica";"><o:p></o:p></span></span></span></div>
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<span style="font-family: "helvetica";"><span style="font-size: large;"><br /></span></span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-family: "helvetica";"><span style="font-size: large;"><br /></span></span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="font-family: "helvetica";">Following the reports of ZIKV infection in
Brazil, the national Ministry of Health (MOH) reported an increase in cases of
microcephaly, a normal rare congenital disorder characterised according to </span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">Estudio
Colaborativo Latino Americano de Malformaciones Congenitas</span><span style="font-family: "helvetica";"> (ECLAMC) initially as a </span><span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US;">small head defined by a
head circumference more than three standard deviations bellow the average in
appropriated charts for sex and age, i.e. a head circumference below 33 cm
(later changed by the Brazilian MOH to 32 cm). </span><span lang="EN-US" style="font-family: "helvetica";"><span style="mso-spacerun: yes;"> </span></span><span style="font-family: "helvetica";">As of January 30 2016, the Brazilian MOH reported
3670 cases being investigated for microcephaly and 404 cases being confirmed
either by clinical signs </span><span lang="EN-US"><span style="color: #191919; font-family: "helvetica";">(congenital
infection,intracranial calcification, dilatation of cerebral ventricles or
changes in the posterior fossa and other clinical signs) or a linkage to ZIKV
infection (maternal and/or fatal).</span></span></span></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgJOqhwv6lr4oAnsDPTdKCeRlIBUqA7J2f7733HsfjhF_timmq2Yntxcocjm3BSQRggNivWz2x1BIIAiXZtNfuPBt86P1jiV2KD0gTowZoYPDU-vqieAWi5bUleDeK967UpHxncy6iA8yJL/s1600/Zika+blog.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgJOqhwv6lr4oAnsDPTdKCeRlIBUqA7J2f7733HsfjhF_timmq2Yntxcocjm3BSQRggNivWz2x1BIIAiXZtNfuPBt86P1jiV2KD0gTowZoYPDU-vqieAWi5bUleDeK967UpHxncy6iA8yJL/s400/Zika+blog.002.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: Reported cases of microcephaly and confirmed cases <br />
in Brazil May 2015- January 2016</td></tr>
</tbody></table>
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<span style="font-size: large;"><span lang="EN-US" style="color: #191919; font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Arial;"><br /></span></span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="color: #191919; font-family: "helvetica"; font-size: large;"><br /></span></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="color: #191919; font-family: "helvetica"; font-size: large;">In contrast, the MOH of Colombia (another
hotspot of confirmed cases of ZIKV) has not reported any increase in
microcephaly cases related to ZIKV despite 2100 pregnant women being infected
with ZIKV, raising the possibility that ZIKV is not the causative agent of
microcephaly in neonates.</span></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<span style="font-family: "helvetica"; font-size: large;">During the epidemic in French Polynesia, an
increase in autoimmune diseases (leucopenia and thrombocytopenic purpura) and
neurological diseases (GBS and meningoencephalitis) as well as a small increase
in microcephaly has been observed, but –as in Brazil- co-infections with both
CHIKV and DENGV are possible, suggesting that ZIKV per se is not causing
microcephaly.</span></div>
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<br /></div>
<div class="MsoNormal" style="text-align: justify; text-justify: inter-ideograph;">
<br /></div>
<div class="MsoNormal" style="line-height: 15.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Times;"><span style="font-size: large;">Several factors may account
for the discrepancy between Brazil and Colombia regarding a link between ZIKV
and the increase in reported microcephaly cases. First, in Brazil the local
SINASC birth database records only 1% of birth defects in live births whereas
the expected percentage is 3%, i.e. birth defects in Brazil are underreported
and with focusing now on a potential link with ZIKV more cases of microcephaly
are reported, fostered not only increased attention of the media but also due
to mandatory reporting. Second, cases of microcephaly always have been higher
in the northeastern region of Brazil. Third, assuming that the number of
pregnant women infected with ZIKV is similar to those infected in the 2007
Yap/Micronesia outbreak, the expected number of microcephaly cases would have
been around 360. The key problem might however the reporting system itself,
since some states report all cases of microcephaly regardless if any link to
ZIKV (either previous infection of the mother or infection of the fetus in
utero) has been shown into the registry that originally was set up to report
only those cases that may be linked to viral infection either of the mother or
the fetus/neonate. Consequently, confirmed cases include also cases without
ZIKV. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="line-height: 15.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Times;"><span style="font-size: large;">In the absence of any ZIKV
vaccine and clear evidence that ZIKV is causing microcephaly however
precautions should be taken. Mass extermination of mosquitoes in Brazil and
other countries will not only combat ZIKV but also other arboviruses such as
Yellow Fever Virus, CHIKV, and DENGV. The number of diagnostic laboratories
needs to be increased and being equipped to detect and distinguish emerging
viruses and the public health system needs to be improved. Funds need to be
make available to care for children born with microcephaly. Given that ZIKV has
been shown to be transmitted by sexual intercourse and blood transfusion,
issues like access to birth control need to be addressed in particular if ZIKV
can be linked to an increase in microcephaly. <o:p></o:p></span></span></div>
<div class="MsoNormal" style="line-height: 15.0pt; margin-bottom: 12.0pt; mso-layout-grid-align: none; mso-pagination: none; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="font-family: "helvetica"; mso-ansi-language: EN-US; mso-bidi-font-family: Times;"><span style="font-size: large;">In order to understand ZIKV,
we need an animal model – not an easy task since ZIKV only replicates in mice
if injected intracelebral. As discussed in a previous post, differences between
strains circulating in Asia and in Africa as well as those circulating in
monkeys need to be addressed as well. Finally the role of transmission of ZIKV via saliva, urine and sexual intercourse needs to be determined as well, although they might only play a minor role compared to the transmission of ZIKV by mosquitoes. Finally so far the focus is on pregnant woman, ignoring the prevalence of ZIKV among cohabiting couples. Future epidemiology however will give us hopefully a full picture of the presence of ZIKV among different socioeconomic groups. <o:p></o:p></span></span></div>
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<br /></div>
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<br /></div>
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<u><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Further reading</span></u></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+bacteriology&rft_id=info%3Apmid%2F13084555&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ultrafiltration+of+recently+isolated+neurotropic+viruses.&rft.issn=0021-9193&rft.date=1953&rft.volume=66&rft.issue=2&rft.spage=173&rft.epage=7&rft.artnum=&rft.au=SMITHBURN+KC&rft.au=BUGHER+JC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+bacteriology&rft_id=info%3Apmid%2F13084555&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ultrafiltration+of+recently+isolated+neurotropic+viruses.&rft.issn=0021-9193&rft.date=1953&rft.volume=66&rft.issue=2&rft.spage=173&rft.epage=7&rft.artnum=&rft.au=SMITHBURN+KC&rft.au=BUGHER+JC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+bacteriology&rft_id=info%3Apmid%2F13084555&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ultrafiltration+of+recently+isolated+neurotropic+viruses.&rft.issn=0021-9193&rft.date=1953&rft.volume=66&rft.issue=2&rft.spage=173&rft.epage=7&rft.artnum=&rft.au=SMITHBURN+KC&rft.au=BUGHER+JC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+bacteriology&rft_id=info%3Apmid%2F13084555&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Ultrafiltration+of+recently+isolated+neurotropic+viruses.&rft.issn=0021-9193&rft.date=1953&rft.volume=66&rft.issue=2&rft.spage=173&rft.epage=7&rft.artnum=&rft.au=SMITHBURN+KC&rft.au=BUGHER+JC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">SMITHBURN KC, & BUGHER JC (1953). Ultrafiltration of recently isolated neurotropic viruses. <span style="font-style: italic;">Journal of bacteriology, 66</span> (2), 173-7 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/13084555" rev="review">13084555</a></span></div>
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<span class="Z3988" style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=BMC+infectious+diseases&rft_id=info%3Apmid%2F26527535&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Potential+of+selected+Senegalese+Aedes+spp.+mosquitoes+%28Diptera%3A+Culicidae%29+to+transmit+Zika+virus.&rft.issn=&rft.date=2015&rft.volume=15&rft.issue=&rft.spage=492&rft.epage=&rft.artnum=&rft.au=Diagne+CT&rft.au=Diallo+D&rft.au=Faye+O&rft.au=Ba+Y&rft.au=Faye+O&rft.au=Gaye+A&rft.au=Dia+I&rft.au=Faye+O&rft.au=Weaver+SC&rft.au=Sall+AA&rft.au=Diallo+M&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=BMC+infectious+diseases&rft_id=info%3Apmid%2F26527535&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Potential+of+selected+Senegalese+Aedes+spp.+mosquitoes+%28Diptera%3A+Culicidae%29+to+transmit+Zika+virus.&rft.issn=&rft.date=2015&rft.volume=15&rft.issue=&rft.spage=492&rft.epage=&rft.artnum=&rft.au=Diagne+CT&rft.au=Diallo+D&rft.au=Faye+O&rft.au=Ba+Y&rft.au=Faye+O&rft.au=Gaye+A&rft.au=Dia+I&rft.au=Faye+O&rft.au=Weaver+SC&rft.au=Sall+AA&rft.au=Diallo+M&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Diagne CT, Diallo D, Faye O, Ba Y, Faye O, Gaye A, Dia I, Faye O, Weaver SC, Sall AA, & Diallo M (2015). Potential of selected Senegalese Aedes spp. mosquitoes (Diptera: Culicidae) to transmit Zika virus. <span style="font-style: italic;">BMC infectious diseases, 15</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26527535" rev="review">26527535</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Transactions+of+the+Royal+Society+of+Tropical+Medicine+and+Hygiene&rft_id=info%3Apmid%2F12995440&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus.+I.+Isolations+and+serological+specificity.&rft.issn=0035-9203&rft.date=1952&rft.volume=46&rft.issue=5&rft.spage=509&rft.epage=20&rft.artnum=&rft.au=DICK+GW&rft.au=KITCHEN+SF&rft.au=HADDOW+AJ&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">DICK GW, KITCHEN SF, & HADDOW AJ (1952). Zika virus. I. Isolations and serological specificity. <span style="font-style: italic;">Transactions of the Royal Society of Tropical Medicine and Hygiene, 46</span> (5), 509-20 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12995440" rev="review">12995440</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Transactions+of+the+Royal+Society+of+Tropical+Medicine+and+Hygiene&rft_id=info%3Apmid%2F13157159&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Zika+virus%3A+a+report+on+three+cases+of+human+infection+during+an+epidemic+of+jaundice+in+Nigeria.&rft.issn=0035-9203&rft.date=1954&rft.volume=48&rft.issue=2&rft.spage=139&rft.epage=45&rft.artnum=&rft.au=MACNAMARA+FN&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">MACNAMARA FN (1954). Zika virus: a report on three cases of human infection during an epidemic of jaundice in Nigeria. <span style="font-style: italic;">Transactions of the Royal Society of Tropical Medicine and Hygiene, 48</span> (2), 139-45 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/13157159" rev="review">13157159</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Memorias+do+Instituto+Oswaldo+Cruz&rft_id=info%3Apmid%2F26061233&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=First+report+of+autochthonous+transmission+of+Zika+virus+in+Brazil.&rft.issn=0074-0276&rft.date=2015&rft.volume=110&rft.issue=4&rft.spage=569&rft.epage=72&rft.artnum=&rft.au=Zanluca+C&rft.au=de+Melo+VC&rft.au=Mosimann+AL&rft.au=Dos+Santos+GI&rft.au=Dos+Santos+CN&rft.au=Luz+K&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Zanluca C, de Melo VC, Mosimann AL, Dos Santos GI, Dos Santos CN, & Luz K (2015). First report of autochthonous transmission of Zika virus in Brazil. <span style="font-style: italic;">Memorias do Instituto Oswaldo Cruz, 110</span> (4), 569-72 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26061233" rev="review">26061233</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Microcephaly in Northeast Brazil: a review of 16208 births between 2012 and 2015</span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">[Submitted] Bull World Health Organ, E-pub: 4 Feb 2016. doi: </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">http://dx.doi.org/10.2471/BLT.16.170639 </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">ECDC (2015)</span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome [Online]. Stockholm: European Centre for Disease Prevention and Control </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">http://ecdc.europa.eu/en/publications/Publications/zika-virus-americas-association-with- microcephaly-rapid-risk-assessment.pdf [Accessed 06/02/2016]</span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">ECLAMC (Estudio Colaborativo Latino Americano de Malformaciones Congénitas)</span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">http://www.eclamc.org</span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Microbes+and+infection+%2F+Institut+Pasteur&rft_id=info%3Apmid%2F26774331&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Autophagy+and+viral+diseases+transmitted+by+Aedes+aegypti+and+Aedes+albopictus.&rft.issn=1286-4579&rft.date=2016&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Carneiro+LA&rft.au=Travassos+LH&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Carneiro LA, & Travassos LH (2016). Autophagy and viral diseases transmitted by Aedes aegypti and Aedes albopictus. <span style="font-style: italic;">Microbes and infection / Institut Pasteur</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26774331" rev="review">26774331</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Euro+surveillance+%3A+bulletin+Europeen+sur+les+maladies+transmissibles+%3D+European+communicable+disease+bulletin&rft_id=info%3Apmid%2F24739982&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Potential+for+Zika+virus+transmission+through+blood+transfusion+demonstrated+during+an+outbreak+in+French+Polynesia%2C+November+2013+to+February+2014.&rft.issn=1025-496X&rft.date=2014&rft.volume=19&rft.issue=14&rft.spage=&rft.epage=&rft.artnum=&rft.au=Musso+D&rft.au=Nhan+T&rft.au=Robin+E&rft.au=Roche+C&rft.au=Bierlaire+D&rft.au=Zisou+K&rft.au=Shan+Yan+A&rft.au=Cao-Lormeau+VM&rft.au=Broult+J&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Musso D, Nhan T, Robin E, Roche C, Bierlaire D, Zisou K, Shan Yan A, Cao-Lormeau VM, & Broult J (2014). Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. <span style="font-style: italic;">Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin, 19</span> (14) PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24739982" rev="review">24739982</a></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Transfusion&rft_id=info%3Apmid%2F26283013&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Inactivation+of+Zika+virus+in+plasma+with+amotosalen+and+ultraviolet+A+illumination.&rft.issn=0041-1132&rft.date=2016&rft.volume=56&rft.issue=1&rft.spage=33&rft.epage=40&rft.artnum=&rft.au=Aubry+M&rft.au=Richard+V&rft.au=Green+J&rft.au=Broult+J&rft.au=Musso+D&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Aubry M, Richard V, Green J, Broult J, & Musso D (2016). Inactivation of Zika virus in plasma with amotosalen and ultraviolet A illumination. <span style="font-style: italic;">Transfusion, 56</span> (1), 33-40 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26283013" rev="review">26283013</a></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Emerging+infectious+diseases&rft_id=info%3Apmid%2F25625872&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Potential+sexual+transmission+of+Zika+virus.&rft.issn=1080-6040&rft.date=2015&rft.volume=21&rft.issue=2&rft.spage=359&rft.epage=61&rft.artnum=&rft.au=Musso+D&rft.au=Roche+C&rft.au=Robin+E&rft.au=Nhan+T&rft.au=Teissier+A&rft.au=Cao-Lormeau+VM&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Musso D, Roche C, Robin E, Nhan T, Teissier A, & Cao-Lormeau VM (2015). Potential sexual transmission of Zika virus. <span style="font-style: italic;">Emerging infectious diseases, 21</span> (2), 359-61 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25625872" rev="review">25625872</a></span> </span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=MMWR.+Morbidity+and+Mortality+Weekly+Report&rft_id=info%3Adoi%2F10.15585%2Fmmwr.mm6505e1er&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Interim+Guidelines+for+Prevention+of+Sexual+Transmission+of+Zika+Virus+%E2%80%94+United+States%2C+2016&rft.issn=0149-2195&rft.date=2016&rft.volume=65&rft.issue=5&rft.spage=1&rft.epage=2&rft.artnum=http%3A%2F%2Fwww.cdc.gov%2Fmmwr%2Fvolumes%2F65%2Fwr%2Fmm6505e1er.htm&rft.au=Oster%2C+A.&rft.au=Brooks%2C+J.&rft.au=Stryker%2C+J.&rft.au=Kachur%2C+R.&rft.au=%2C+.&rft.au=Mead%2C+P.&rft.au=Pesik%2C+N.&rft.au=Petersen%2C+L.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Oster, A., Brooks, J., Stryker, J., Kachur, R., , ., Mead, P., Pesik, N., & Petersen, L. (2016). Interim Guidelines for Prevention of Sexual Transmission of Zika Virus — United States, 2016 <span style="font-style: italic;">MMWR. Morbidity and Mortality Weekly Report, 65</span> (5), 1-2 DOI: <a href="http://dx.doi.org/10.15585/mmwr.mm6505e1er" rev="review">10.15585/mmwr.mm6505e1er</a></span>
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thelonevirologisthttp://www.blogger.com/profile/09724187674862325697noreply@blogger.com0tag:blogger.com,1999:blog-8715161762555608131.post-53306903305181859672016-01-31T21:08:00.000-05:002016-01-31T21:08:09.124-05:00Zika Virus (ZIKV): similarities to other arboviruses <div class="MsoNormal" style="mso-layout-grid-align: none; mso-pagination: none; tab-stops: 28.0pt 56.0pt 84.0pt 112.0pt 140.0pt 168.0pt 196.0pt 224.0pt 252.0pt 280.0pt 308.0pt 336.0pt; text-align: justify; text-autospace: none; text-justify: inter-ideograph;">
<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Z</span></span><span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">ika Virus (ZIKV) is an arbovirus belonging to the <i>Flaviviridae</i>
transmitted primarily by mosquitoes (including <i>Aedes Agypti </i>and<i> Aedes albopictus</i>).
Although first identified in a rhesus monkey from the forests in Uganda in the
year 1947 -with an estimated first emergence probably in 1920- the first human
case was only reported in 1952 in Nigeria. ZIKV has been shown to be
distributed Northern Africa as well as in Southeast Asia and the Pacific;
however only a few human cases in Africa and Asia were identified until 2007,
when a ZIKV outbreak was reported in Yap/Micronesia followed by an outbreak in
French Polynesia and New Caledonia 2013 and currently in Central and South America
as well as the Caribbean. <o:p></o:p></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Most epidemiological studies that are based on the
seroprevalence of neutralizing antibodies, suggest that up to 73% of the
population (6.1-73%) have been exposed to ZIKV.<o:p></o:p></span></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjumuzrWoXeCyqkJjAdAd29dR2dPpViYUJU5h9SNA2Fz2EW2NOwLS7w-EjPpK60eWE9k_GY6YAWxtCaG9uoI8y3gpKXWJLS0hjupGsZ28-WVkZp5Es7ZMfsNVr8Lm66S2_stGeNeSA60FcG/s1600/Zika+Virus+Blog.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjumuzrWoXeCyqkJjAdAd29dR2dPpViYUJU5h9SNA2Fz2EW2NOwLS7w-EjPpK60eWE9k_GY6YAWxtCaG9uoI8y3gpKXWJLS0hjupGsZ28-WVkZp5Es7ZMfsNVr8Lm66S2_stGeNeSA60FcG/s400/Zika+Virus+Blog.001.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table 1: Outbreaks of ZIKV in Africa, Asia and the Pacific prior 2016 and seroprevalence of<br />ZIKV </td></tr>
</tbody></table>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Being a Flavivirus, ZIKV -like the related West Nile
Virus (WNV), Japanese Encephalitis Virus (JEV), Chikungunya (CHIKV) and Dengue
Virus (DENGV)- has a single strand, positive sense RNA genome, encoding for a
polyprotein that ultimately is processed into three structural proteins, the
Capsid (C), precursor of Membrane protein (prM), and Envelope (E) protein as
well as seven non-structural proteins (NS1-5). <o:p></o:p></span></span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjAHSY4PwTht6gaIx7O_BSU4Uokmi_r4bLK-JuT5KmBVoAGrhYj5F1iTTp3uRduPf2YgfIhvEeS2m6ycA0eM7Z1xa1NjPBExPf5GpZEl1XaeqW3rRPsehb_QkUXtKCtyTBk-iwiX1_gz8LX/s1600/Zika+Virus+Blog.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjAHSY4PwTht6gaIx7O_BSU4Uokmi_r4bLK-JuT5KmBVoAGrhYj5F1iTTp3uRduPf2YgfIhvEeS2m6ycA0eM7Z1xa1NjPBExPf5GpZEl1XaeqW3rRPsehb_QkUXtKCtyTBk-iwiX1_gz8LX/s400/Zika+Virus+Blog.002.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV structure</td></tr>
</tbody></table>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEikmw13SdTPWSbKWC89yg3OU3i1gbPBtuniDFUfNEp9DKdmEzwo6zHqlHXFLJZZrnYN3oH0B7UNuQAilUC_1q1JgpnJCcmhVlHaXmfeK0JT0old_SOYwTUjs4PVRlOi9MTktxWggDHyUOKE/s1600/Zika+Virus+Blog.003.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEikmw13SdTPWSbKWC89yg3OU3i1gbPBtuniDFUfNEp9DKdmEzwo6zHqlHXFLJZZrnYN3oH0B7UNuQAilUC_1q1JgpnJCcmhVlHaXmfeK0JT0old_SOYwTUjs4PVRlOi9MTktxWggDHyUOKE/s400/Zika+Virus+Blog.003.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV polyprotein</td></tr>
</tbody></table>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiMV-2_3V7HJiTAeWSSaSuNC9N1L6kckh8aHllW583d5cYil0w1nW3lwBviwVRCjWtmltYjISd9LPZZs3_9Mga5RGK_C5sc0OBsEwpF4YbR5OijuapeeGCbpLnfVurfUmm8Yd2t7XdsG9Uu/s1600/Zika+Virus+Blog.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiMV-2_3V7HJiTAeWSSaSuNC9N1L6kckh8aHllW583d5cYil0w1nW3lwBviwVRCjWtmltYjISd9LPZZs3_9Mga5RGK_C5sc0OBsEwpF4YbR5OijuapeeGCbpLnfVurfUmm8Yd2t7XdsG9Uu/s400/Zika+Virus+Blog.004.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table 2: ZIKV proteins</td></tr>
</tbody></table>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to CHIKV, the infection with ZIKV is a
relative mild disease, characterised symptoms ranging from mild fever,
headaches, conjunctivitis, maculopapular rashes, vertigo, or myalgia with low
mortality and often is asymptomatic. <o:p></o:p></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Since the clinical presentation is similar to
infections with other arboviruses, in particular CHIKV and DENGV, diagnostics
is difficult and mostly done by using RT-PCR of samples that are CHIKV and
DENGV negative. Although serological tests (ELISA, Immunofluorescence) have
been used in the past, they are less reliable due to cross-reactivity with
other flaviviruses such as DENGV or Yellow Fever Virus. Currently no commercial
kit is available to test for ZIKV in patients.<o:p></o:p></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Being transmitted by infected mosquitoes, the initial
target cells are in the skin compartment, both skin fibroblasts, epidermal
keratinocytes and dendritic cells are highly permissible for ZIKV which enters
the host cell a number cellular receptors, in particular DC-SIGN, AXL, Tyro-3,
and (albeit to a lesser extent) TIM-1. Primary skin fibroblasts infected with
ZIKV support viral replication whereas in infected primary epidermal
keratinocytes, similar to keratinocytes infected with DENV, exhibit large
cytoplasmic vacuolation and pyknotic nuclei can be observed, suggesting that
ZIKV induces apoptosis in these cells despite supporting viral replication. <o:p></o:p></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Similar to JEV and CHIKV infected cell, ZIKV induces
the formation of autophagosome-like structure that form the scaffold for the
assembly of viral replication centres. If the expression of the viral preE2/E1
and Capsid proteins also induces ER stress (similar to CHIKV) and if the ER
stress induced by ZIKV contributes to the induction of autophagy and/or caspase
dependent apoptosis has not been demonstrated yet, but seems to be very likely. </span></span><br />
<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiqFRcQ6wWwluLjvhkh1xCw0MJpQcsiTGQcgJez4ByCYSy-SW_98QT1vq7FNx9fRiIYpbXzclB3iJqZio2AMVXJxIzqIvbccNyW-cW-ued5xmr4XJh_RM1EFys3wfIvsV42bWg4s5oYdSvj/s1600/Zika+Virus+Blog.006.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiqFRcQ6wWwluLjvhkh1xCw0MJpQcsiTGQcgJez4ByCYSy-SW_98QT1vq7FNx9fRiIYpbXzclB3iJqZio2AMVXJxIzqIvbccNyW-cW-ued5xmr4XJh_RM1EFys3wfIvsV42bWg4s5oYdSvj/s400/Zika+Virus+Blog.006.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: CHIKV and the ER stress response</td></tr>
</tbody></table>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjJAXISVtXGpeuVIwlok737L7-fqyWOC1BEAzVKPEjwxKmwltXDZEnIbjo9GMWF76NABr_HLqfWS44yPEzMDltaJNwyEDcimqv2eTfc6nMAGl4xxc9lr94TvwEipknn0MUMM-YRVvEMid2_/s1600/Zika+Virus+Blog.007.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjJAXISVtXGpeuVIwlok737L7-fqyWOC1BEAzVKPEjwxKmwltXDZEnIbjo9GMWF76NABr_HLqfWS44yPEzMDltaJNwyEDcimqv2eTfc6nMAGl4xxc9lr94TvwEipknn0MUMM-YRVvEMid2_/s400/Zika+Virus+Blog.007.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: JEV and the ER stress response</td></tr>
</tbody></table>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi4gOIIW1an1o0RXVc0vusPqih4oTUxCQqL31Emu3ofs-1k1pdVFeQiryPzZdXKZejk1TmrGQ9J558Y62XFYv_AcGKgRgKUCyILvbgnP-_djLurc9GJvy6RWxhKHRK_j4v8nuphDRTQBqtn/s1600/Zika+Virus+Blog.009.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi4gOIIW1an1o0RXVc0vusPqih4oTUxCQqL31Emu3ofs-1k1pdVFeQiryPzZdXKZejk1TmrGQ9J558Y62XFYv_AcGKgRgKUCyILvbgnP-_djLurc9GJvy6RWxhKHRK_j4v8nuphDRTQBqtn/s400/Zika+Virus+Blog.009.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: JEV and the induction of autophagosome formation via non-structural and structural<br />proteins located at the ER</td></tr>
</tbody></table>
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</div>
<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Likewise it has not been demonstrated if the formation of autophagosomes by
ZIKV in primary skin fibroblasts is -as in the case of CHIKV- dependent on
LC3-C and NDP52. Given that only the Asian lineage, in contrast to the African
lineage, of ZIKV has been able to cause prolonged epidemics in the human
populations (in 2007 and currently in the Americas) it has been speculated that
the viral NS1 gene adaptions increases viral fitness in humans. Therefore, it
might be necessary to investigate the ability of different isolates from
different lineages to induce the formation of replication centres in primary
human cells. If the decrease in autophagic flux or viral induced ER stress in
infected primary dermal and skin cells or in keratinocytes induces apoptosis
has not been demonstrated.<o:p></o:p></span></span></div>
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<div class="separator" style="clear: both; text-align: center;">
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhN6fRj7ua9y08IU6CrOeti_4oh6Lz_Gf5fjDClEhHWnkRG-EZDsTLbUK3AOZlgEcqtQ4IHNtBJjX2IRB0EAUzKGTTlj5niujLP5tg0cNkC8bnKo8cIPtvKCwB6v59A2UgVwJjjK3TBlys5/s1600/Zika+Virus+Blog.010.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhN6fRj7ua9y08IU6CrOeti_4oh6Lz_Gf5fjDClEhHWnkRG-EZDsTLbUK3AOZlgEcqtQ4IHNtBJjX2IRB0EAUzKGTTlj5niujLP5tg0cNkC8bnKo8cIPtvKCwB6v59A2UgVwJjjK3TBlys5/s400/Zika+Virus+Blog.010.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV induction of the antiviral response</td></tr>
</tbody></table>
<br /></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><b>Antiviral response induced by ZIKV : role of the antiviral interferon response</b></span><br />
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><b><br /></b></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In primary skin cells, following viral entry and
release of the viral genome, the viral RNA induces the transcription of
Interferon stimulated genes (ISG) such as OAS2, MX1, and ISG15, as well as the
transcription of RIG-1, MDA-5, and Toll-like receptor (TLR-3) in a Interferon-β
(IFN-β).As a result, viral replication is inhibited. <o:p></o:p></span></span></div>
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<span style="font-family: 'helvetica neue', arial, helvetica, sans-serif; font-size: large;">Since the infection of primary human dermal
fibroblasts and primary human foreskin fibroblast cells (HFF) with ZIKV also
induces the formation of LC3-II positive membrane vesicles , it might be
possible that TLR-3 mediated NF-κB signaling induces autophagy in a DRAM-1
dependent manner.</span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">If these vesicles however represent viral replication
centres or are involved in antiviral signaling by degrading viral components
(or are even involved in the presentation of viral antigens<span style="mso-spacerun: yes;"> </span>via the MHC- Class I and II complexes) is not
clear. <o:p></o:p></span></span><br />
<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiv36S-SwKVoAa1zoFDHkwxXTzy7JiWScqNu1oFIept7Mqvgjt7eJsnIAIAE5c_J1hxcxICk1bexnY810KVP1wRmFV9ece6IuDhAQj2HvEIX_LcJGXMF91R6GYmQK9RCYTUfmM33I_-W2Uw/s1600/Zika+Virus+Blog.011.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiv36S-SwKVoAa1zoFDHkwxXTzy7JiWScqNu1oFIept7Mqvgjt7eJsnIAIAE5c_J1hxcxICk1bexnY810KVP1wRmFV9ece6IuDhAQj2HvEIX_LcJGXMF91R6GYmQK9RCYTUfmM33I_-W2Uw/s400/Zika+Virus+Blog.011.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: TLR-3 and autophagy; formation of autophagosomes via DRAM-1</td></tr>
</tbody></table>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The intracelebral inoculation of mice with ZIKV
results in productive viral replication in both neuronal and astroglial cells,
with autophagosome-like structures present that resemble viral replication
centres. A subset of infected cells however has been shown to undergo necrosis,
suggesting that the infection of neuronal cells with ZIKV -similar to human
medullablastoma TE-671 cells, astrocytes and neuronal cells infected with JEV-
induces both the formation of autophagosome-like structures as well as cell
death. If however ZIKV induced cell death is dependent on the induction of
caspase-3 and -9 in addition to ROS dependent activation of apoptosis signaling
kinase (ASK)-1 and p38 MAPK signaling pathways has not been demonstrated.
Despite the close proximity of ZIKV replication centres, an involvement of the
ER stress response in the formation of ZIKV RC has not been demonstrated as
well.<o:p></o:p></span></span><br />
<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><b> ZIKV and the nucleolus</b></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">As discussed in a previous post, a number of viral
proteins localises to the nucleolus, thus (potentially) inducing the formation
of autophagosomes and/or inducing via activation of p53. In the case of the
small isoform of West Nile Virus (WNV) Capsid protein for instance, p53
dependent apoptosis is induced by sequestration of Hdm2 to the nucleolus whilst
the large isoform inhibits apoptosis and activates mTOR-dependent p70S6K, thus
inducing translation of viral genes. If either isoform, affects also the formation
of LC3-II positive vesicles has not been demonstrated; it should be noted
however that the NS4A and NS4B proteins from all WNV isolates (except NY99)
induce autophagy as a result of ER stress. Since the NS4B protein derived from
the WNV Kunjin subtype also localises to the nucleolus, an involvement of the
nucleolus in the formation of WNV RC cannot be ruled out. <o:p></o:p></span></span><br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjO8sxIAks5NT5-3kS-0fC-Lc1oCbF3QcJ7y_dh-YqTp7Waltf3mMStbantDBAzoH5d-cDwMPSgKvwDbwx7UZmTgom3Ofy2C08PUZ6REwHs12vsg2CCwKFK_CE7tV8faII3ooDayzaKKNKd/s1600/Zika+Virus+Blog.012.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjO8sxIAks5NT5-3kS-0fC-Lc1oCbF3QcJ7y_dh-YqTp7Waltf3mMStbantDBAzoH5d-cDwMPSgKvwDbwx7UZmTgom3Ofy2C08PUZ6REwHs12vsg2CCwKFK_CE7tV8faII3ooDayzaKKNKd/s400/Zika+Virus+Blog.012.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Table3: Flavivirus proteins that localise to the nucleolus</td></tr>
</tbody></table>
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">It might therefore possible that the nucleolar localisation of ZIKV protein(s) might induce a cell cycle delay, promote apoptosis or induce autophagy. </span> </div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><b><br /></b></span>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-IJZusXJ_lePG4Kq2snYaqUvvWWFI_pJMELdrS_DntRrygfWtabJ_l72VQMyMDBJmB5TP0AqTw3TnGbqZY9JTjwNT2W64D2Fle2cTlzqvtK09dAhUfnpwIE9-4FJdl-ZEKNZ-6DsHHwD7/s1600/Zika+Virus+Blog.013.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-IJZusXJ_lePG4Kq2snYaqUvvWWFI_pJMELdrS_DntRrygfWtabJ_l72VQMyMDBJmB5TP0AqTw3TnGbqZY9JTjwNT2W64D2Fle2cTlzqvtK09dAhUfnpwIE9-4FJdl-ZEKNZ-6DsHHwD7/s400/Zika+Virus+Blog.013.jpeg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Figure: ZIKV might promote autophagy or induce apoptosis by sequestering p53 </td></tr>
</tbody></table>
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><b><br /></b></span>
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><b><br /></b></span>
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><b> ZIKV, Microcephaly, and Guillan-Barre Syndrome</b></span><br />
<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><b><br /></b></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In the case of viral induced microcephaly, <i>in utero</i>
infection with Human Cytomegalovirus (HCMV) has been associated with cases of
microcephaly in newborn infants, but if ZIKV is a causative agent of
microcephaly as well or if other factors -such as co-infection of pregnant
women with other neurotrophic viruses such as DENGV or CHIKV, and/or parasites
such as malaria as well as environmental factors despite the isolation of viral
RNA from the placenta and amniotic fluid also play a role is not clear.<o:p></o:p></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">During the current outbreak of ZIKV in the Americas as
well as during the outbreak of ZIKV in French Polynesia, an increase in
patients exhibiting Guillan-Barre Syndrome (GBS), a rare neurological disorder
caused by an autoimmune response, has been reported. Although so far no direct
link between ZIKV and GBS has been reported, it might be possible that the
decrease in autophagic flux in ZIKV infected neuronal cells induces apoptosis
or if the observed increase is related to an autoimmune response as a result of
the immune response (as in cases of rheumatoid arthritis in CHIKV positive
patients) remains to be seen.<o:p></o:p></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">In summary, based on results published on other
members of the <i>Flaviviridae, </i>ZIKV might exhibit similar features
regarding the interaction with host cell, including the formation of
replication centres by inducing the ER stress response, the localisation of
viral proteins to the nucleolus and -probably most importantly-the induction of
antiviral Interferon signaling via the induction of TLR-3 mediated NF-κB signaling
(that might also induce the formation of autophagosomes, supporting viral
replication and/or degrading viral proteins and RNA) and the induction of
Interferon stimulated genes (ISG), thus inhibiting viral replication. </span><span style="font-family: "helvetica";"><o:p></o:p></span></span></div>
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<a href="http://www.researchblogging.org/" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img alt="ResearchBlogging.org" src="http://www.researchblogging.org/public/citation_icons/rb2_large_gray.png" style="border: 0px;" /></a><span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span></div>
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<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><br /></span></span>
<span lang="EN-US" style="color: black;"><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><u>Further reading</u></span></span><br />
<br /></div>
<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Medecine+et+maladies+infectieuses&rft_id=info%3Apmid%2F25001879&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Current+Zika+virus+epidemiology+and+recent+epidemics.&rft.issn=0399-077X&rft.date=2014&rft.volume=44&rft.issue=7&rft.spage=302&rft.epage=7&rft.artnum=&rft.au=Ioos+S&rft.au=Mallet+HP&rft.au=Leparc+Goffart+I&rft.au=Gauthier+V&rft.au=Cardoso+T&rft.au=Herida+M&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"></span><br />
<div style="text-align: justify;">
<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Medecine+et+maladies+infectieuses&rft_id=info%3Apmid%2F25001879&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Current+Zika+virus+epidemiology+and+recent+epidemics.&rft.issn=0399-077X&rft.date=2014&rft.volume=44&rft.issue=7&rft.spage=302&rft.epage=7&rft.artnum=&rft.au=Ioos+S&rft.au=Mallet+HP&rft.au=Leparc+Goffart+I&rft.au=Gauthier+V&rft.au=Cardoso+T&rft.au=Herida+M&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, & Herida M (2014). Current Zika virus epidemiology and recent epidemics. <span style="font-style: italic;">Medecine et maladies infectieuses, 44</span> (7), 302-7 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25001879" rev="review">25001879</a></span></div>
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<div style="text-align: justify;">
<span style="font-family: 'Helvetica Neue', Arial, Helvetica, sans-serif; font-size: large;">Jan C, Languillat G, Renaudet J, & Robin Y (1978). [A serological survey of arboviruses in Gabon]. </span><span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span style="font-style: italic;">Bulletin de la Societe de pathologie exotique et de ses filiales, 71</span> (2), 140-6 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/743766" rev="review">743766</a></span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cellular+microbiology&rft_id=info%3Apmid%2F17697133&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=West+Nile+virus+capsid+protein+induces+p53-mediated+apoptosis+via+the+sequestration+of+HDM2+to+the+nucleolus.&rft.issn=1462-5814&rft.date=2008&rft.volume=10&rft.issue=1&rft.spage=165&rft.epage=76&rft.artnum=&rft.au=Yang+MR&rft.au=Lee+SR&rft.au=Oh+W&rft.au=Lee+EW&rft.au=Yeh+JY&rft.au=Nah+JJ&rft.au=Joo+YS&rft.au=Shin+J&rft.au=Lee+HW&rft.au=Pyo+S&rft.au=Song+J&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Cellular+microbiology&rft_id=info%3Apmid%2F17697133&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=West+Nile+virus+capsid+protein+induces+p53-mediated+apoptosis+via+the+sequestration+of+HDM2+to+the+nucleolus.&rft.issn=1462-5814&rft.date=2008&rft.volume=10&rft.issue=1&rft.spage=165&rft.epage=76&rft.artnum=&rft.au=Yang+MR&rft.au=Lee+SR&rft.au=Oh+W&rft.au=Lee+EW&rft.au=Yeh+JY&rft.au=Nah+JJ&rft.au=Joo+YS&rft.au=Shin+J&rft.au=Lee+HW&rft.au=Pyo+S&rft.au=Song+J&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Yang MR, Lee SR, Oh W, Lee EW, Yeh JY, Nah JJ, Joo YS, Shin J, Lee HW, Pyo S, & Song J (2008). West Nile virus capsid protein induces p53-mediated apoptosis via the sequestration of HDM2 to the nucleolus. <span style="font-style: italic;">Cellular microbiology, 10</span> (1), 165-76 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/17697133" rev="review">17697133</a></span> </span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F24920798&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=West+nile+virus-induced+activation+of+mammalian+target+of+rapamycin+complex+1+supports+viral+growth+and+viral+protein+expression.&rft.issn=0022-538X&rft.date=2014&rft.volume=88&rft.issue=16&rft.spage=9458&rft.epage=71&rft.artnum=&rft.au=Shives+KD&rft.au=Beatman+EL&rft.au=Chamanian+M&rft.au=O%27Brien+C&rft.au=Hobson-Peters+J&rft.au=Beckham+JD&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions"><br /></span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F24920798&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=West+nile+virus-induced+activation+of+mammalian+target+of+rapamycin+complex+1+supports+viral+growth+and+viral+protein+expression.&rft.issn=0022-538X&rft.date=2014&rft.volume=88&rft.issue=16&rft.spage=9458&rft.epage=71&rft.artnum=&rft.au=Shives+KD&rft.au=Beatman+EL&rft.au=Chamanian+M&rft.au=O%27Brien+C&rft.au=Hobson-Peters+J&rft.au=Beckham+JD&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Shives KD, Beatman EL, Chamanian M, O'Brien C, Hobson-Peters J, & Beckham JD (2014). West nile virus-induced activation of mammalian target of rapamycin complex 1 supports viral growth and viral protein expression. <span style="font-style: italic;">Journal of virology, 88</span> (16), 9458-71 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/24920798" rev="review">24920798</a></span> </span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+virology&rft_id=info%3Apmid%2F23115297&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+West+Nile+virus+capsid+protein+blocks+apoptosis+through+a+phosphatidylinositol+3-kinase-dependent+mechanism.&rft.issn=0022-538X&rft.date=2013&rft.volume=87&rft.issue=2&rft.spage=872&rft.epage=81&rft.artnum=&rft.au=Urbanowski+MD&rft.au=Hobman+TC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Urbanowski MD, & Hobman TC (2013). The West Nile virus capsid protein blocks apoptosis through a phosphatidylinositol 3-kinase-dependent mechanism. <span style="font-style: italic;">Journal of virology, 87</span> (2), 872-81 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/23115297" rev="review">23115297</a></span> </span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Frontiers+in+microbiology&rft_id=info%3Apmid%2F25642225&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Amino+acid+substitutions+in+the+non-structural+proteins+4A+or+4B+modulate+the+induction+of+autophagy+in+West+Nile+virus+infected+cells+independently+of+the+activation+of+the+unfolded+protein+response.&rft.issn=&rft.date=2014&rft.volume=5&rft.issue=&rft.spage=797&rft.epage=&rft.artnum=&rft.au=Bl%C3%A1zquez+AB&rft.au=Mart%C3%ADn-Acebes+MA&rft.au=Saiz+JC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Blázquez AB, Martín-Acebes MA, & Saiz JC (2014). Amino acid substitutions in the non-structural proteins 4A or 4B modulate the induction of autophagy in West Nile virus infected cells independently of the activation of the unfolded protein response. <span style="font-style: italic;">Frontiers in microbiology, 5</span> PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25642225" rev="review">25642225</a></span> </span></div>
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<span style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Journal+of+general+virology&rft_id=info%3Apmid%2F21228127&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=A+West+Nile+virus+mutant+with+increased+resistance+to+acid-induced+inactivation.&rft.issn=0022-1317&rft.date=2011&rft.volume=92&rft.issue=Pt+4&rft.spage=831&rft.epage=40&rft.artnum=&rft.au=Mart%C3%ADn-Acebes+MA&rft.au=Saiz+JC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Martín-Acebes MA, & Saiz JC (2011). A West Nile virus mutant with increased resistance to acid-induced inactivation. <span style="font-style: italic;">The Journal of general virology, 92</span> (Pt 4), 831-40 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21228127" rev="review">21228127</a></span>
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Autophagy&rft_id=info%3Apmid%2F25946067&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Reconciling+West+Nile+virus+with+the+autophagic+pathway.&rft.issn=1554-8627&rft.date=2015&rft.volume=11&rft.issue=5&rft.spage=861&rft.epage=4&rft.artnum=&rft.au=Mart%C3%ADn-Acebes+MA&rft.au=Bl%C3%A1zquez+AB&rft.au=Saiz+JC&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Martín-Acebes MA, Blázquez AB, & Saiz JC (2015). Reconciling West Nile virus with the autophagic pathway. <span style="font-style: italic;">Autophagy, 11</span> (5), 861-4 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/25946067" rev="review">25946067</a></span> </span></div>
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<span class="Z3988" style="font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+Australian+%26+New+Zealand+journal+of+obstetrics+%26+gynaecology&rft_id=info%3Apmid%2F26391432&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Congenital+cytomegalovirus+infection+in+pregnancy%3A+a+review+of+prevalence%2C+clinical+features%2C+diagnosis+and+prevention.&rft.issn=0004-8666&rft.date=2016&rft.volume=56&rft.issue=1&rft.spage=9&rft.epage=18&rft.artnum=&rft.au=Naing+ZW&rft.au=Scott+GM&rft.au=Shand+A&rft.au=Hamilton+ST&rft.au=van+Zuylen+WJ&rft.au=Basha+J&rft.au=Hall+B&rft.au=Craig+ME&rft.au=Rawlinson+WD&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CVirology+Cell+Biology+VirusHost+Interactions">Naing ZW, Scott GM, Shand A, Hamilton ST, van Zuylen WJ, Basha J, Hall B, Craig ME, & Rawlinson WD (2016). Congenital cytomegalovirus infection in pregnancy: a review of prevalence, clinical features, diagnosis and prevention. <span style="font-style: italic;">The Australian & New Zealand journal of obstetrics & gynaecology, 56</span> (1), 9-18 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/26391432" rev="review">26391432</a></span>
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