The role of progesterone in barrier responses to intravaginal viral infection.

Abstract

Abstract The female reproductive tract (FRT) is a robust physical and immunological barrier tasked with balancing tolerogenic immunity to non-self antigens such as commensal bacteria, sperm, and fetal tissues, with protection against sexually transmitted pathogens such as herpes simplex virus (HSV) and Zika virus (ZIKV). The FRT is dynamically regulated by hormones, but the mechanisms by which hormones affect antiviral responses in immune and non-immune cells are incompletely understood. We found that a high progesterone state, such as pregnancy or treatment with Depo-medroxyprogesterone acetate (DMPA, Depo-provera), was necessary to render mice susceptible to vaginal infection with HSV-1 or ZIKV, and that this was true for both wild-type and immunocompromised Ifnar1−/− mice. The effect of progesterone was specific to vaginal infection as treatment with DMPA did not enhance susceptibility to HSV or ZIKV infection by dermal or subcutaneous inoculation, respectively. Importantly, we found that only DMPA-treated mice were protected against secondary vaginal infection, suggesting that productive viral replication is necessary for the establishment of protective memory responses in the vagina. Although we found that DMPA increased dye permeability of the vagina, mechanical abrasion without DMPA treatment was not sufficient to induce susceptibility, implicating other roles of progesterone in modulating epithelial antiviral responses. Together, these data underscore a crucial endocrine-immune axis involved in early antiviral responses in the vagina. Ongoing studies seek to identify progesterone-responsive cells in the vagina and to define the mechanism by which progesterone renders these cells permissive to viral infection. Supported by grants from NIH K12-GM000678 (SJD), NIH F31 AI143237 (CAL), NIH R01 AI139512 (HML), and NIH R21 AI44631 (HML).