Development of a novel mouse model with progesterone-independent susceptibility to genital HSV infection

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Genital herpes, an incurable sexually transmitted infection (STI) caused by herpes simplex virus (HSV), disproportionately affects women and can cause sex-specific adverse events such as increased risk of acquiring other STIs as well as vertical transmission during birth. The mouse is commonly used as a preclinical model to study immunity and pathogenesis of vaginal HSV infection. However, one major drawback of the murine model is that unlike humans, mice are susceptible to infection only at certain stages of the estrus cycle. Thus, female mice are typically pre-treated with depot medroxyprogesterone acetate (DMPA, Depo-Provera), a progesterone-based hormonal contraceptive, to hold the mice in diestrus and ensure uniform susceptibility to HSV infection. However, the use of DMPA limits the study of host-pathogen interactions a single stage of the estrus cycle, despite abundant evidence that female sex hormones have a major impact on antiviral defense and immunosurveillance of the female reproductive tract. Furthermore, use of DMPA precludes co-inoculation studies with commensal bacteria or fungi, as these microbes often require an estrogen-high environment to robustly colonize the murine vagina. One major difference between the mouse and human vagina is that expression of the viral entry receptor nectin-1 on epithelial cells is hormone dependent in mice, but constitutively expressed in humans. To overcome this challenge, this proposal will develop a novel mouse model in which nectin-1 is constitutively expressed in the murine vaginal epithelium by addressing transcriptional and post-translational regulatory mechanisms. Nectin-1 expression will be placed under the control two different constitutive promoters, and two mutations will be introduced to prevent ectodomain cleavage. Epithelium-specific expression of nectin-1 will be achieved through the inclusion of a stop-flox cassette and breeding to mice in which Cre recombinase expression is controlled by the human keratin 14 promoter. Finally, the HSV susceptibility of these novel mice will be tested at different stages of the estrus cycle. The successful development of a novel, more translational mouse model of HSV infection would help achieve our long-term goal of exploring the role of sex hormones in modulating host-pathogen interactions at the vaginal barrier as well as investigating the molecular impact of vaginal microbial dysbiosis or STI co- infection on HSV pathogenesis. We expect future studies to reveal unknown aspects of protective immunity against genital herpes, including that induced by vaccines, and potentially lead to the discovery of novel targets for therapeutics aimed at reducing susceptibility against HSV infection.