Nicole Navratil, MS
29 April 2016
Zika virus has become a significant international concern due to a potential association between the virus and birth defects such as microcephaly1 and the neurological disorder Gillian-Barré Syndrome.2 The virus reached the Americas in early 2015 when it was detected in Brazil. It has since been reported in several other countries and continues to spread. To date, over 350 cases have been reported in the continental United States, each associated with travel.Locally acquired infections have been recorded in the US territories of American Samoa, Puerto Rico and the US Virgin Islands.3
Zika virus is spread by the mosquito species Aedes aegypti and Aedes albopictus, which are commonly found in tropical, subtropical and some temperate climates. The virus can also be sexually transmitted from men to their partners, and transmitted through blood transfusion.4 There is currently no vaccine, and the recent spread of the disease has prompted expedited vaccine efforts.5
There is now evidence that mice deficient for interferon receptors, including A129 and AG129 mice, can be valuable for evaluating the efficacy of new vaccines and antiviral treatments for Zika Virus.A129 mice lack the receptor for IFN-α/β (type I interferon), and AG129 mice lack receptors for IFN-α/β as well as receptors for IFN-γ (type II interferon).
It is clear that IFN-α/β plays a significant role in preventing viral replication and protecting against Zika virus disease. A recent study by Lazear and colleagues evaluated several mice strains lacking key components of innate antiviral immunity, and they found that those mice who did not respond to IFN-α/β or who produced very little IFN-α/β were all highly susceptible to Zika virus infection.6 Furthermore, Rossi and colleagues recently characterized both A129 and AG129 mice as models for evaluating Zika virus and successfully demonstrated viral replication and disease in both models.7 This group also observed neurological symptoms in the AG129 mice, not observed in the A129 mice, suggesting the possibility that IFN-γ may provide protection against Zika virus infection in neurological tissues. 7 An evaluation of Zika virus infection in AG129 mice by Aliota and colleagues also reported significant histopathology of the brain.8 These observations could suggest relevance to the disease pathogenesis in humans, including the possible association between Zika virus and effects on the CNS such as with Guillain-Barré Syndrome and microcephaly.
Dowall and colleagues also evaluated the effect of Zika virus on A129 mice, and they suggested that the model provides advantages for understanding the adaptive immune response since they retain the INF-γ response.9 None of the immunocompetent controls utilized in these studies, including C57BL/66, C57BL/6J7, CD17, and 129Sv/Ev9 demonstrated clinical symptoms of disease. Dowall and colleagues did, however, initially detect Zika virus in the blood, ovaries and spleen of infected control 129sv/Ev mice with no clinical symptoms. They suggest there may be potential for the use of these mice for evaluating teratogenic effects since the virus was present in the circulating blood, but the animals did not succumb to disease or mortality.9
Three studies also documented viral replication and high viral load in the testes of the IFN-α/β deficient mice, demonstrating additional possible relevance to understanding human pathogenesis since sexual transmission from infected men has been documented in humans. 6, 7, 10
Mice deficient for IFN-α/β and INF-γ may provide useful tools for evaluating drugs and vaccines to combat Zika virus. Zmurko and colleagues have already evaluated the potential of various compounds that have antiviral effects on similar viruses, and they demonstrated that the viral polymerase inhibitor 7DMA (7-deaza-2'-C-methyladenosine) was well tolerated in AG129 mice infected with Zika virus, and with daily treatment it delayed disease progression and reduced the viral load detected in serum of those mice.10
While significantly more work and additional animal models will be required to fully understand the pathogenesis of Zika virus disease in humans and other species, A129 and AG129 mice can provide a very useful tool for addressing this growing pandemic.
1. Mlaker J, Korva M, Til N, Popovic M, Poljsak-Prijatelj M, Mraz J, Kolenc M, Rus KR, Vipotnik TV, Vodusek VF, Vizjak A, Pizem J, Petrovec M, Zupanc TA. (2016). Zika virus associated with microcephaly. N Engl J Med, 374: 951-958. http://dx.doi.org/10.1056/NEJMoa1600651
2. Cao-Lormea V-M, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, Dub T, Baudouin L Teissier A, Larre P, Vial A-L, Decam C, Choumet V, Halstead S, Willison HJ, Musset L, Manuguerra J-C, Despres P, Fournier E, Mallet H-P, Musso D, Fontanet A, Neil J Ghawche F. (2016). Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. The Lancet, 387(10027): p1531–1539. Published online February 29, 2016. http://dx.doi.org/10.1016/S0140-6736(16)00562-6
3. Center for Disease Control and Prevention. (2016, April 27). Zika Virus Disease in the United States, 2015-2016. http://www.cdc.gov/zika/geo/united-states.html
4. Center for Disease Control and Prevention. (2016, April 15). Transmission & Risks. http://www.cdc.gov/zika/transmission/index.html
5. Hayden EC (2016, March 28). The Race is on to Develop Zika Vaccine. Nature News. http://www.nature.com/news/the-race-is-on-to-develop-zika-vaccine-1.19634
6. 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, 1-11. Published online April 5, 2016. http://dx.doi.org/10.1016/j.chom.2016.03.010
7. Rossi SL, Tesh RB, Azar SR, Muruato AE, Hanley KA, Auguste AJ, Langsjoen RM, Paessler S, Basilaski N, Weaver SC. (2016). Characterization of a novel murine model to study zika virus. Am J Trop Med Hyg, 16-0111; Published online March 28, 2016. http://dx.doi.org/10.4269/ajtmh.16-0111
8. Aliota MT, Caine EA, Walker EC, Larkin KE, Camacho E, Osorio JE. (2016). Characterization of lethal Zika virus infection in AG129 mice. PLoS Negl Trop Dis, 10(4). Published online April 19, 2016. http://dx.doi.org/10.1371/journal.pntd.0004682
9. Dowall SD, Graham VA, Ratner E, Atkinson B, Hall G, Watson RJ, Bosworth A, Bonney LC, Kitchen S, Hewson R. (2016) A susceptible mouse model for Zika virus infection. bioRxiv. Published online March 4, 2016. http://dx.doi.org/10.1101/042358
10. Zmurko J, Marques RE, Schols D, Verbeken E, Kaptein SJF, Neyts. (2016) The viral polymerase inhibitor 7-deaza-2'-C-methyladenosine is a potent inhibitor of in 1 vitro Zika virus replication and delays disease progression in a robust mouse infection model. bioRxiv. Published online March 1, 2016. http://dx.doi.org/10.1101/041905