Zika Virus (ZIKV) is a mosquitoe born member of the Flaviviridae 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.
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 do notsupport viral replication 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.
These and other questions however underline the
necessity for an animal model.
ZIKV
animal model: AG129 mice
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 in vitro studies using brain organoids
and hNPC.
More recently, 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.
These findings are supported by observations in
AG129 mice that are deficient for Interferon (IFN)-α /-β/- γ 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.
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.
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.
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.
Further reading
Ioos, S., Mallet, H., Leparc Goffart, I., Gauthier, V., Cardoso, T., & Herida, M. (2014). Current Zika virus epidemiology and recent epidemics Médecine et Maladies Infectieuses, 44 (7), 302-307 DOI: 10.1016/j.medmal.2014.04.008
Sarno M, Sacramento GA, Khouri R, do Rosário MS, Costa F, Archanjo G, Santos LA, Nery N Jr, Vasilakis N, Ko AI, & de Almeida AR (2016). Zika Virus Infection and Stillbirths: A Case of Hydrops Fetalis, Hydranencephaly and Fetal Demise. PLoS neglected tropical diseases, 10 (2) PMID: 26914330
Chan JF, Choi GK, Yip CC, Cheng VC, & Yuen KY (2016). Zika fever and congenital Zika syndrome: An unexpected emerging arboviral disease. The Journal of infection, 72 (5), 507-24 PMID: 26940504
Hamel R, Liégeois F, Wichit S, Pompon J, Diop F, Talignani L, Thomas F, Desprès P, Yssel H, & Missé D (2016). Zika virus: epidemiology, clinical features and host-virus interactions. Microbes and infection / Institut Pasteur PMID: 27012221
Lazear HM, & Diamond MS (2016). Zika Virus: New Clinical Syndromes and Its Emergence in the Western Hemisphere. Journal of virology, 90 (10), 4864-75 PMID: 26962217
de Paula Freitas B, de Oliveira Dias JR, Prazeres J, Sacramento GA, Ko AI, Maia M, & Belfort R Jr (2016). Ocular Findings in Infants With Microcephaly Associated With Presumed Zika Virus Congenital Infection in Salvador, Brazil. JAMA ophthalmology PMID: 26865554
Hazin AN, Poretti A, Cruz DD, Tenorio M, van der Linden A, Pena LJ, Brito C, Gil LH, Miranda-Filho DB, Marques ET, Martelli CM, Alves JG, Huisman TA, & Microcephaly Epidemic Research Group (2016). Computed Tomographic Findings in Microcephaly Associated with Zika Virus. The New England journal of medicine PMID: 27050112
Broutet N, Krauer F, Riesen M, Khalakdina A, Almiron M, Aldighieri S, Espinal M, Low N, & Dye C (2016). Zika Virus as a Cause of Neurologic Disorders. The New England journal of medicine, 374 (16), 1506-9 PMID: 26959308
Lednicky J, Beau De Rochars VM, El Badry M, Loeb J, Telisma T, Chavannes S, Anilis G, Cella E, Ciccozzi M, Rashid M, Okech B, Salemi M, & Morris JG Jr (2016). Zika Virus Outbreak in Haiti in 2014: Molecular and Clinical Data. PLoS neglected tropical diseases, 10 (4) PMID: 27111294
Faria NR, Azevedo Rdo S, Kraemer MU, Souza R, Cunha MS, Hill SC, Thézé J, Bonsall MB, Bowden TA, Rissanen I, Rocco IM, Nogueira JS, Maeda AY, Vasami FG, Macedo FL, Suzuki A, Rodrigues SG, Cruz AC, Nunes BT, Medeiros DB, Rodrigues DS, Nunes Queiroz AL, da Silva EV, Henriques DF, Travassos da Rosa ES, de Oliveira CS, Martins LC, Vasconcelos HB, Casseb LM, Simith Dde B, Messina JP, Abade L, Lourenço J, Carlos Junior Alcantara L, de Lima MM, Giovanetti M, Hay SI, de Oliveira RS, Lemos Pda S, de Oliveira LF, de Lima CP, da Silva SP, de Vasconcelos JM, Franco L, Cardoso JF, Vianez-Júnior JL, Mir D, Bello G, Delatorre E, Khan K, Creatore M, Coelho GE, de Oliveira WK, Tesh R, Pybus OG, Nunes MR, & Vasconcelos PF (2016). Zika virus in the Americas: Early epidemiological and genetic findings. Science (New York, N.Y.), 352 (6283), 345-9 PMID: 27013429
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.) PMID: 27064148
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 PMID: 26952870
Brown, M., McAlpine, S., Huang, Y., Haidl, I., Al-Afif, A., Marshall, J., & Anderson, R. (2012). RNA Sensors Enable Human Mast Cell Anti-Viral Chemokine Production and IFN-Mediated Protection in Response to Antibody-Enhanced Dengue Virus Infection PLoS ONE, 7 (3) DOI: 10.1371/journal.pone.0034055
Wahala, W., & de Silva, A. (2011). The Human Antibody Response to Dengue Virus Infection Viruses, 3 (12), 2374-2395 DOI: 10.3390/v3122374
Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, Puttikhunt C, Edwards C, Duangchinda T, Supasa S, Chawansuntati K, Malasit P, Mongkolsapaya J, & Screaton G (2010). Cross-reacting antibodies enhance dengue virus infection in humans. Science (New York, N.Y.), 328 (5979), 745-8 PMID: 20448183
Aliota MT, Caine EA, Walker EC, Larkin KE, Camacho E, & Osorio JE (2016). Characterization of Lethal Zika Virus Infection in AG129 Mice. PLoS neglected tropical diseases, 10 (4) PMID: 27093158
Schultz KL, Vernon PS, & Griffin DE (2015). Differentiation of neurons restricts Arbovirus replication and increases expression of the alpha isoform of IRF-7. Journal of virology, 89 (1), 48-60 PMID: 25320290
Schultz KL, Vernon PS, & Griffin DE (2015). Differentiation of neurons restricts Arbovirus replication and increases expression of the alpha isoform of IRF-7. Journal of virology, 89 (1), 48-60 PMID: 25320290
Kulcsar KA, Baxter VK, Abraham R, Nelson A, & Griffin DE (2015). Distinct Immune Responses in Resistant and Susceptible Strains of Mice during Neurovirulent Alphavirus Encephalomyelitis. Journal of virology, 89 (16), 8280-91 PMID: 26041298
Atkins GJ, & Sheahan BJ (2016). Molecular Determinants of Alphavirus Neuropathogenesis in Mice. The Journal of general virology PMID: 27028153
Adibi JJ, Marques ET Jr, Cartus A, & Beigi RH (2016). Teratogenic effects of the Zika virus and the role of the placenta. Lancet (London, England), 387 (10027), 1587-90 PMID: 26952548
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