Zika Virus (ZIKV) is an
emerging flavivirus that was first isolated in 1947 from a sentinel 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 only caused mild disease
in humans with up to 80% of asymptomatic cases.
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 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.
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.
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.
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 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.
Consequently, recently published studies which have been discussed in extensio 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 cells as well
as two foetal cell lines. 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). 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 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.
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.
Antiviral
drugs: targeting caspase-3
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.
 |
| Figure: Effect of tested compounds on cell viability of ZIKV infected cells (Astrocytes, SNB-19 glioblastoma cells and hNPC) Negative cell viablity=toxic effect even in absence of ZIKV |
 |
| Figure: Effect of tested compounds on ZIKV induced caspase-3 activity |
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.
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 PHA-690509, Niclosamide and Seliciclib 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 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 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 in
utero. Cdki however might be useful in treating adults, preventing sexual
transmission and/or prolonged shedding of ZIKV in urine, saliva and tears.
 |
| Figure: (A) Niclosamide: targeting viral entry (B) Cdki: targeting multiple cdk |
ZIKV
and the cell cycle: G2 and mitotic arrest
As
discussed in a previous post, the in
utero 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 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 intermediate zone (IZ/SP), all of which
contain PCNA positive proliferating cells and VIM positive RGC cells, of ex vivo 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.
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.
In 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 the centrosomal protein CEP170 and the mitotic
apparatus protein NuMA as well as g-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.
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.
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-beta, 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.
 |
| Figure: ZIKV and DENV-1/-2/-4 NS4A and TBK-1 mediated signalling: targeting phosphorylation of IRF-3 |
Apart
from inhibiting mitotic progression, interfering with TBK-1 dependent immune
signalling 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.
 |
| Table: Genes related to mitotic progression that are up- or downregulated in ZIKV MR766 infected hNPC |
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 -since ZIKV infects neuronal cells- 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 aberrant S-phase entry
of postmitotic neurons.
In addition 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.
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.
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. 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.
 |
| Figure: Hypothetical network of ZIKV induced changes to the cell cycle in infected cells |
Further reading
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. Cell host & microbe, 20 (2), 259-70 PMID: 27476412
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. Cell host & microbe, 20 (2), 259-70 PMID: 27476412
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. PLoS neglected tropical diseases, 10 (6) PMID: 27341420
Campos Rde M, Cirne-Santos C, Meira GL, Santos LL, de Meneses MD, Friedrich J, Jansen S, Ribeiro MS, da Cruz IC, Schmidt-Chanasit J, & Ferreira DF (2016). Prolonged detection of Zika virus RNA in urine samples during the ongoing Zika virus epidemic in Brazil. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 77, 69-70 PMID: 26921737
Chatel-Chaix L, Cortese M, Romero-Brey I, Bender S, Neufeldt CJ, Fischl W, Scaturro P, Schieber N, Schwab Y, Fischer B, Ruggieri A, & Bartenschlager R (2016). Dengue Virus Perturbs Mitochondrial Morphodynamics to Dampen Innate Immune Responses. Cell host & microbe, 20 (3), 342-56 PMID: 27545046
Costa F, Sarno M, Khouri R, de Paula Freitas B, Siqueira I, Ribeiro GS, Ribeiro HC, Campos GS, Alcântara LC, Reis MG, Weaver SC, Vasilakis N, Ko AI, & Almeida AR (2016). Emergence of Congenital Zika Syndrome: Viewpoint From the Front Lines. Annals of internal medicine, 164 (10), 689-91 PMID: 26914810
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. Nature, 534 (7606), 267-71 PMID: 27279226
DICK GW (1953). Epidemiological notes on some viruses isolated in Uganda; Yellow fever, Rift Valley fever, Bwamba fever, West Nile, Mengo, Semliki forest, Bunyamwera, Ntaya, Uganda S and Zika viruses. Transactions of the Royal Society of Tropical Medicine and Hygiene, 47 (1), 13-48 PMID: 13077697
DICK GW (1952). Zika virus. II. Pathogenicity and physical properties. Transactions of the Royal Society of Tropical Medicine and Hygiene, 46 (5), 521-34 PMID: 12995441
DICK GW, KITCHEN SF, & HADDOW AJ (1952). Zika virus. I. Isolations and serological specificity. Transactions of the Royal Society of Tropical Medicine and Hygiene, 46 (5), 509-20 PMID: 12995440
Garcez PP, Loiola EC, Madeiro da Costa R, Higa LM, Trindade P, Delvecchio R, Nascimento JM, Brindeiro R, Tanuri A, & Rehen SK (2016). Zika virus impairs growth in human neurospheres and brain organoids. Science (New York, N.Y.), 352 (6287), 816-8 PMID: 27064148
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. Cell reports, 15 (11), 2315-22 PMID: 27268504
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. JCI insight, 1 (13) PMID: 27595140
Lazear HM, Govero J, Smith AM, Platt DJ, Fernandez E, Miner JJ, & Diamond MS (2016). A Mouse Model of Zika Virus Pathogenesis. Cell host & microbe, 19 (5), 720-30 PMID: 27066744
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. Cell stem cell PMID: 27545505
Miner JJ, & Diamond MS (2016). Understanding How Zika Virus Enters and Infects Neural Target Cells. Cell stem cell, 18 (5), 559-60 PMID: 27152436
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. Cell reports, 16 (12), 3208-18 PMID: 27612415
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. Cell stem cell, 18 (5), 591-6 PMID: 27038591
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. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin, 19 (9) PMID: 24626205
Onorati M, Li Z, Liu F, Sousa AM, Nakagawa N, Li M, Dell'Anno MT, Gulden FO, Pochareddy S, Tebbenkamp AT, Han W, Pletikos M, Gao T, Zhu Y, Bichsel C, Varela L, Szigeti-Buck K, Lisgo S, Zhang Y, Testen A, Gao XB, Mlakar J, Popovic M, Flamand M, Strittmatter SM, Kaczmarek LK, Anton ES, Horvath TL, Lindenbach BD, & Sestan N (2016). Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell reports, 16 (10), 2576-92 PMID: 27568284
Paploski IA, Prates AP, Cardoso CW, Kikuti M, Silva MM, Waller LA, Reis MG, Kitron U, & Ribeiro GS (2016). Time Lags between Exanthematous Illness Attributed to Zika Virus, Guillain-Barré Syndrome, and Microcephaly, Salvador, Brazil. Emerging infectious diseases, 22 (8), 1438-44 PMID: 27144515
Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, Yao B, Hamersky GR, Jacob F, Zhong C, Yoon KJ, Jeang W, Lin L, Li Y, Thakor J, Berg DA, Zhang C, Kang E, Chickering M, Nauen D, Ho CY, Wen Z, Christian KM, Shi PY, Maher BJ, Wu H, Jin P, Tang H, Song H, & Ming GL (2016). Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. Cell, 165 (5), 1238-54 PMID: 27118425
Ribeiro LS, Marques RE, Jesus AM, Almeida RP, & Teixeira MM (2016). Zika crisis in Brazil: challenges in research and development. Current opinion in virology, 18, 76-81 PMID: 27179929
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. Cell stem cell, 18 (5), 587-90 PMID: 26952870
Weaver SC, Costa F, Garcia-Blanco MA, Ko AI, Ribeiro GS, Saade G, Shi PY, & Vasilakis N (2016). Zika virus: History, emergence, biology, and prospects for control. Antiviral research, 130, 69-80 PMID: 26996139
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. Cell research, 26 (6), 645-54 PMID: 27174054
Xu, M., Lee, E., Wen, Z., Cheng, Y., Huang, W., Qian, X., TCW, J., Kouznetsova, J., Ogden, S., Hammack, C., Jacob, F., Nguyen, H., Itkin, M., Hanna, C., Shinn, P., Allen, C., Michael, S., Simeonov, A., Huang, W., Christian, K., Goate, A., Brennand, K., Huang, R., Xia, M., Ming, G., Zheng, W., Song, H., & Tang, H. (2016). Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen Nature Medicine DOI: 10.1038/nm.4184
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. Nucleic acids research PMID: 27580721
Rohn TT, Wirawan E, Brown RJ, Harris JR, Masliah E, & Vandenabeele P (2011). Depletion of Beclin-1 due to proteolytic cleavage by caspases in the Alzheimer's disease brain. Neurobiology of disease, 43 (1), 68-78 PMID: 21081164
Wirawan E, Vande Walle L, Kersse K, Cornelis S, Claerhout S, Vanoverberghe I, Roelandt R, De Rycke R, Verspurten J, Declercq W, Agostinis P, Vanden Berghe T, Lippens S, & Vandenabeele P (2010). Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell death & disease, 1 PMID: 21364619
Zhou A, Li S, Khan FA, & Zhang S (2016). Autophagy postpones apoptotic cell death in PRRSV infection through Bad-Beclin1 interaction. Virulence, 7 (2), 98-109 PMID: 26670824
Zhu Y, Zhao L, Liu L, Gao P, Tian W, Wang X, Jin H, Xu H, & Chen Q (2010). Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis. Protein & cell, 1 (5), 468-77 PMID: 21203962 Dalrymple, N., Cimica, V., & Mackow, E. (2015). Dengue Virus NS Proteins Inhibit RIG-I/MAVS Signaling by Blocking TBK1/IRF3 Phosphorylation: Dengue Virus Serotype 1 NS4A Is a Unique Interferon-Regulating Virulence Determinant mBio, 6 (3) DOI: 10.1128/mBio.00553-15
Phoolcharoen W, & Smith DR (2004). Internalization of the dengue virus is cell cycle modulated in HepG2, but not Vero cells. Journal of medical virology, 74 (3), 434-41 PMID: 15368519
Thepparit C, & Smith DR (2004). Serotype-specific entry of dengue virus into liver cells: identification of the 37-kilodalton/67-kilodalton high-affinity laminin receptor as a dengue virus serotype 1 receptor. Journal of virology, 78 (22), 12647-56 PMID: 15507651
Chattopadhyay S, Marques JT, Yamashita M, Peters KL, Smith K, Desai A, Williams BR, & Sen GC (2010). Viral apoptosis is induced by IRF-3-mediated activation of Bax. The EMBO journal, 29 (10), 1762-73 PMID: 20360684
Sharif-Askari E, Nakhaei P, Oliere S, Tumilasci V, Hernandez E, Wilkinson P, Lin R, Bell J, & Hiscott J (2007). Bax-dependent mitochondrial membrane permeabilization enhances IRF3-mediated innate immune response during VSV infection. Virology, 365 (1), 20-33 PMID: 17451770
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 Nature Communications, 6 DOI: 10.1038/ncomms10072
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. Proceedings of the National Academy of Sciences of the United States of America, 113 (15), 4039-44 PMID: 27035970
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 Nature Immunology, 10 (11), 1215-1221 DOI: 10.1038/ni.1800
No comments:
Post a Comment