Characterization of Lethal Zika Virus Infection in AG129 Mice.

Matthew T Aliota,Erwin Camacho,Emma C Walker,Elizabeth A Caine,Jorge E Osorio,Katrina E Larkin,Eva Harris

doi:10.1371/journal.pntd.0004682

Matthew T Aliota, Erwin Camacho + Show 5 more

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https://doi.org/10.1371/journal.pntd.0004682

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Abstract

BackgroundMosquito-borne Zika virus (ZIKV) typically causes a mild and self-limiting illness known as Zika fever, which often is accompanied by maculopapular rash, headache, and myalgia. During the current outbreak in South America, ZIKV infection during pregnancy has been hypothesized to cause microcephaly and other diseases. The detection of ZIKV in fetal brain tissue supports this hypothesis. Because human infections with ZIKV historically have remained sporadic and, until recently, have been limited to small-scale epidemics, neither the disease caused by ZIKV nor the molecular determinants of virulence and/or pathogenicity have been well characterized. Here, we describe a small animal model for wild-type ZIKV of the Asian lineage.Methodology/Principal FindingsUsing mice deficient in interferon α/β and Ɣ receptors (AG129 mice), we report that these animals were highly susceptible to ZIKV infection and disease, succumbing within seven to eight days. Rapid viremic dissemination was observed in visceral organs and brain; but only was associated with severe pathologies in the brain and muscle. Finally, these results were consistent across challenge routes, age of mice, and inoculum doses. These data represent a mouse model for ZIKV that is not dependent on adapting ZIKV to intracerebral passage in mice.Conclusions/SignificanceFoot pad injection of AG129 mice with ZIKV represents a biologically relevant model for studying ZIKV infection and disease development following wild-type virus inoculation without the requirement for adaptation of the virus or intracerebral delivery of the virus. This newly developed Zika disease model can be exploited to identify determinants of ZIKV virulence and reveal molecular mechanisms that control the virus-host interaction, providing a framework for rational design of acute phase therapeutics and for vaccine efficacy testing.

Highlights

Zika virus (ZIKV; Flaviviridae, Flavivirus) has emerged out of Africa and caused outbreaks of febrile disease in Yap islands of the Federated states of Micronesia [1], French Polynesia [2], and Oceania; and in late 2015 Brazil reported the first known local transmission of ZIKV in the Americas [3]
Mosquito-borne Zika virus (ZIKV) typically causes a mild and self-limiting illness known as Zika fever, which often is accompanied by maculopapular rash, headache, and myalgia
ZIKV infection typically causes a mild and self-limiting illness known as Zika fever, which often is accompanied by maculopapular rash, headache, and myalgia

Summary

Introduction

Zika virus (ZIKV; Flaviviridae, Flavivirus) has emerged out of Africa and caused outbreaks of febrile disease in Yap islands of the Federated states of Micronesia [1], French Polynesia [2], and Oceania; and in late 2015 Brazil reported the first known local transmission of ZIKV in the Americas [3]. The virus is believed to have originated in Africa, where it still circulates enzootically among unknown vertebrate hosts (presumably nonhuman primates), and is transmitted by arboreal Aedes mosquitoes [9,10]. These cycles lead to sporadic outbreaks of spillover infection in Africa, but most human cases around the globe result from ZIKV emergence into a human-mosquito cycle involving Aedes aegypti [11] and/or other urban or peri-urban Aedes species, e.g., Aedes albopictus and Aedes hensilli [1,12,13]. We describe a small animal model for wild-type ZIKV of the Asian lineage

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