Interferon Epsilon Signaling Confers Attenuated Zika Replication in Human Vaginal Epithelial Cells

Zika virus (ZIKV) is an emerging flavivirus that causes congenital birth defects and neurological compilations in the human host. Although ZIKV is primarily transmitted through infected mosquitos, recent studies reveal sexual contact as a potential transmission route. In vagina-bearing individuals, the vaginal epithelium constitutes the first line of defense against viruses. However, it is unclear how ZIKV interacts with the vaginal epithelium to initiate ZIKV transmission. In this study, we demonstrate that exposing ZIKV to human vaginal epithelial cells (hVECs) resulted in de novo viral RNA replication, increased envelope viral protein production, and a steady, extracellular release of infectious viral particles. Interestingly, our data show that, despite an increase in viral load, the hVECs did not exhibit significant cytopathology in culture as other cell types typically do. Furthermore, our data reveal that the innate antiviral state of hVECs plays a crucial role in preventing viral cytopathology. For the first time, our data show that interferon epsilon inhibits ZIKV replication. Collectively, our results in this study provide a novel perspective on the viral susceptibility and replication dynamics during ZIKV infection in the human vaginal epithelium. These findings will be instrumental towards developing therapeutic agents aimed at eliminating the pathology caused by the virus.