The impact of dynamic mucosal baseline immune states on C. muridarum and N. gonorrhoeae infection outcomes in a murine menstruation model 3775

Abstract Description Although the menstrual cycle influences the risk of acquiring sexually transmitted infections (STIs), the underlying immune contributions are poorly defined. A mouse model simulating the immune-mediated process of endometrial remodeling and menstruation could provide critical insights into tissue-specific immune determinants of protection. Here, we developed a repeat pseudopregnancy approach for inducing cyclical menstruation in C57BL6 mice and performed vaginal challenge with Chlamydia muridarum or Neisseria gonorrhoeae (strain FA1090) during the time frame of endometrial remodeling or repair. This strategy identified that uterine repair correlated with robust infections, greater bacterial burdens, and tissue damage, while challenges during endometrial remodeling were protective. Cellular and soluble immune profiling over pseudopregnancy identified proinflammatory oscillations, including IFNγ-driven NK cell recruitment into the cervicovaginal tissues as a result of endometrial remodeling, which we translationally validated using pig-tailed macaques. Notably, NK cell depletion during endometrial remodeling reversed protection, with mice now productively infected. This study shows that murine menstruation models recapitulate dynamic immune changes occurring throughout the reproductive tract and identify NK cell localization in the cervicovaginal lumen under menstrual cycle regulation as essential for immune protection against primary infections. Funding Sources Supported by NIH/NAIAD R21AI180610 Topic Categories Mucosal and Regional Immunology (MUC)