Examination of protective mucosal immune responses to viral sexually transmitted infections
Abstract
Sexually transmitted infections (STI) are a prominent global health issue that affect the sexual and reproductive health of billions worldwide. Viral STIs present a particular challenge due to limited availability of treatment options and their frequent establishment of lifelong infection. One of the most common viral STIs is genital herpes, a recurrent ulcerative disease caused by chronic infection with the human alphaherpesviruses, HSV-1 or HSV-2. Women are particularly susceptible to morbidities of infection ranging from increased risk of HIV-1 acquisition to vertical transfer to neonates, for whom infection can be fatal. Previous efforts to develop a prophylactic vaccine for genital herpes have failed in part due to limited understanding of the mechanisms required for protective immunity in the vagina, which is a primary portal of entry for STIs. Furthermore, most investigation into host responses to genital HSV infection has historically only focused on HSV-2. Little is known about immunity during genital HSV-1 infection despite its rising prevalence across the globe and known differences in disease outcomes. To address these questions and more, we use an established female mouse model of genital herpes to study vaginal immunity during primary HSV infection. Through direct comparisons of HSV-1 and HSV-2 vaginal infection, we seek to identify differences in the innate and adaptive immune response to each virus that determine neuronal infection and mucosal pathology outcomes. From these studies, we determined that HSV-1 triggers a faster innate immune response in the vagina than HSV-2, promoting earlier effector T cell responses and enhanced viral control in both the vagina and peripheral nervous system in an IFN-dependent manner. Rapid vaginal NK cell activation after HSV-1 infection appeared to be a distinguishing factor, aiding faster dendritic cell migration and maturation in the draining lymph nodes. Further investigation into the underexplored vaginal NK cell compartment also revealed an unexpected role in restricting genital skin and vaginal mucosal epithelium damage in coordination with neutrophils during HSV-1 infection. This was in stark contrast to the excessive immunopathology caused by neutrophils during HSV-2 infection. Together, these studies contribute deeper understanding of host immunity to two forms of genital herpes infections and reveal insights regarding protective immune mechanisms in the vagina more broadly.