Sexual and Vertical Transmission of Zika Virus in anti-interferon receptor-treated Rag1-deficient mice

Clayton W Winkler,Tyson A Woods,Dana P Scott,Sonja M Best,Rebecca Rosenke,Karin E Peterson

doi:10.1038/s41598-017-07099-7

Abstract

Although Zika virus (ZIKV) is primarily transmitted to humans by the Aedes aegypti mosquito, human-to-human transmission has also been observed from males-to-females as well as mother-to-offspring. In the current study, we studied both sexual transmission (STx) and vertical transmission (VTx) of ZIKV using anti-IFNAR1-treatment of Rag1−/− (AIR) mice. These mice have suppressed type I IFN responses and lack adaptive immune responses, leading to a prolonged infection prior to clinical disease. STx of ZIKV from infected AIR males to naive Ifnar1−/− females was observed with greater than 50% incidence, with infection observed in the vaginal tract at early time points. In the case of a resulting pregnancy, virus was also found in the uterus and placental tissue. In additional studies, VTx of virus was observed in AIR female mice. Specifically, peripheral ZIKV infection of pregnant AIR females resulted in detectable virus in brain and/or lymph nodes of fetuses and/or pups. VTx of ZIKV was stochastic, in that not all fetuses/pups within the same dam had detectable virus and infection was not associated with breakdown of maternal/fetal placental barrier. This provides a new model to study the barriers to STx and VTx of ZIKV and the immune responses essential to preventing transmission.

Highlights

Zika Virus (ZIKV) is a flavivirus, originally isolated in Uganda, but more recently associated with outbreaks in both South and North America
VTx was observed in approximately 26% of fetuses/pups, with virus detected in focal areas of Sox2+ neuroprogenitor cells in central nervous system (CNS) tissue
These results are similar to those observed with other VTx models including Zika virus (ZIKV)-infection of Ifnar1−/− mice or SJL mice, but exclude the potential complications of severe weight loss associated with ZIKV-infection of Ifnar1−/− mice[8] or the high inoculating dose required to overcome the IFN response in SJL mice[15]

Summary

Introduction

Zika Virus (ZIKV) is a flavivirus, originally isolated in Uganda, but more recently associated with outbreaks in both South and North America. VTx of ZIKV has been observed in Ifnar1−/− mice, with infection inducing dramatic fetal insufficiency by [13,14,15] days of embryonic development[11] These studies indicate that the IFN response is critical for preventing STx and VTx. further studies are needed to demonstrate the potential for STx and VTx in models where the IFN response is suppressed rather than incompetent, as is the case in humans. ZIKV-infected Ifnar1−/− mice have severe weight loss by [6,7] dpi[8] This delay in disease onset in AIR mice provides a longer window to study transmission of virus during the earlier stages of virus infection. We demonstrated STx of virus from ZIKV-infected AIR male to Ifnar1−/− female mice. Transmission primarily occurred during a specific time frame post-infection in males, suggesting efficiency of STx is finite

Methods

Results

Conclusion