Zika virus replicates in the vagina of mice with intact interferon signaling

Abstract

Zika virus (ZIKV) is unusual among flaviviruses in its ability to spread between humans through sexual contact, as well as by mosquitoes. Sexual transmission has the potential to change the epidemiology and geographic range of ZIKV compared to mosquito-borne transmission and potentially could produce distinct clinical manifestations, so it is important to understand the host mechanisms that control susceptibility to sexually transmitted ZIKV. ZIKV replicates poorly in wild-type mice following subcutaneous inoculation, so most ZIKV pathogenesis studies use mice lacking IFN-{beta} signaling (e.g. Ifnar1-/-). However, we found that wild-type mice support ZIKV replication following intravaginal infection, although the infection remained localized to the lower female reproductive tract. Vaginal replication was not a unique property of ZIKV, as other flaviviruses that generally are restricted in wild-type mice also were able to replicate in the vagina. Vaginal ZIKV infection required a high-progesterone state (pregnancy or pre-treatment with depot medroxyprogesterone acetate (DMPA)), identifying a key role for hormonal status in susceptibility to vaginal infection. Progesterone-mediated susceptibility did not appear to result from a compromised epithelial barrier, blunted antiviral gene induction, or changes in vaginal leukocyte populations, leaving open the mechanism by which progesterone confers susceptibility to vaginal ZIKV infection. Progesterone treatment is a key component of mouse vaginal infection models for herpes simplex virus and Chlamydia, but the mechanisms by which DMPA increases susceptibility to those pathogens also remain poorly defined. Understanding how progesterone mediates susceptibility to ZIKV vaginal infection may provide insights into host mechanisms influencing susceptibility to diverse sexually transmitted pathogens. IMPORTANCEZika virus (ZIKV) is transmitted by mosquitoes, similarly to other flaviviruses. However, ZIKV is unusual in its ability also to spread through sexual transmission. We found that ZIKV was able to replicate in the vaginas of wild-type mice, even though these mice do not support ZIKV replication by other routes, suggesting that the vagina is particularly susceptible to ZIKV infection. Vaginal susceptibility was dependent on a high progesterone state, which is a common feature of mouse vaginal infection models for other pathogens, through mechanisms that have remained poorly defined. Understanding how progesterone mediates susceptibility to ZIKV vaginal infection may provide insights into host mechanisms that influence susceptibility to diverse sexually transmitted pathogens.