Vivian Diep

Introduction. The 1947 discovery of Zika Virus (ZIKV) in Uganda has evolved from sporadic outbreaks to a global health emergency. ZIKV is an Aedes mosquito-borne flaviviridae and its presentation resembles that of other arboviruses such as dengue. Studies have shown that in addition to flu-like symptoms, ZIKV can lead to complications such as congenital microcephaly and Guillain-Barre Syndrome due to its neurotropism. Furthermore, beyond the Aedes vector, ZIKV has also demonstrated trans-placental and sexual transmission.^1-4 Currently, available treatments are mainly symptomatic and there is no vaccine. However, Type I Interferon has been shown to be neuroprotective in animal studies.^2,5,6 Further understanding of ZIKV pathogenesis and utilization of animal models can advance efforts to discover more effective interventions.¹ Methods. Animal models including mice and rhesus macaques were utilized. Rhesus macaques were inoculated with ZIKV to observe acute (1-3 days) and persistent (35 days) presentations. Blood, urine, and tissue samples were collected to determine tropism.^3,4 Wild-type and interferon receptor knockout (IFNAR) mice were inoculated with ZIKV to determine the efficacy of the intrinsic fast type I interferon response.^2,5 Dexamethasone-immunosuppressed mice were inoculated with ZIKV and administered recombinant Type I Interferon treatment to evaluate clinical outcomes.⁶ Results. Humans and rhesus macaques share a more similar biology then rodents, making macaques an appropriate animal model to evaluate ZIKV clinical manifestations. Acute observations included few symptoms and vRNA only detectable in hemolymphatic tissues.³ Upon persistent infection, vRNA was detectable in the central nervous system and reproductive tissues, along with a more severe sequelae.⁴ After ZIKV inoculation in wild-type mice, astrocytes mounted a rapid interferon response establishing an antiviral state that suppressed viral replication. IFNAR mice did not mount the same response and subsequently had severe symptoms such as bilateral limb paralysis.^2,5 Immunosuppressed mice inoculated with ZIKV and administered recombinant Type I pegylated interferon demonstrated lower viral loads, fewer symptoms, and less inflammatory infiltrate than those who did not receive treatment.⁶ Conclusions. The lack of severe symptoms during acute ZIKV episodes suggests that direct infection is required for disease pathogenesis. Intrinsic interferon induction indicates that establishing a basal antiviral state is vital in delaying invasion into tissues and the onset of debilitating symptoms. Furthermore, administering recombinant interferon treatment may delay ZIKV cytopathic effects in patients or act as a prophylactic treatment for the immunocompromised. Overall, establishing interferon regimens may help slow global ZIKV progression and generate more time for the production of a viable vaccine.

1. Chan JF-W, Yip CC-Y, Tsang JO-L, et al. Differential cell line susceptibility to the emerging Zika virus: implications for disease pathogenesis, non-vector-borne human transmission and animal reservoirs. Emerging Microbes & Infections. 2016;5(8):e93-. doi:10.1038/emi.2016.99.
2. Manangeeswaran M, Ireland DDC, Verthelyi D. Zika (PRVABC59) Infection Is Associated with T cell Infiltration and Neurodegeneration in CNS of Immunocompetent Neonatal C57Bl/6 Mice. Klein RS, ed. PLoS Pathogens. 2016;12(11):e1006004. doi:10.1371/journal.ppat.1006004.
3. Coffey LL, Pesavento PA, Keesler RI, Singapuri A, Watanabe J, Watanabe R, et al. (2017) Zika Virus Tissue and Blood Compartmentalization in Acute Infection of Rhesus Macaques. PLoS ONE 12(1): e0171148. doi:10.1371/journal. pone.0171148
4. Hirsch AJ, Smith JL, Haese NN, Broeckel RM, Parkins CJ, Kreklywich C, et al. (2017) Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues. PLoS Pathog 13(3):e1006219.doi:10.1371/journal.ppat.1006219
5. Lindqvist R, Mundt F, Gilthorpe JD, et al. Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects. Journal of Neuroinflammation. 2016;13:277. doi:10.1186/s12974-016-0748-7.
6. Chan JF-W, Zhang AJ, Chan CC-S, et al. Zika Virus Infection in Dexamethasone-immunosuppressed Mice Demonstrating Disseminated Infection with Multi-organ Involvement Including Orchitis Effectively Treated by Recombinant Type I Interferons. EBioMedicine. 2016;14:112-122. doi:10.1016/j.ebiom.2016.11.017.