Murine modeling of menstruation identifies immune correlates of protection duringChlamydia muridarumchallenge
Authors: Lawrence Laurel A. , Vidal Paola , Varughese Richa S. , Li Zheng-Rong Tiger , Chen Thien Duy , Tuske Steven C. , Jimenez Ariana R. , Lowen Anice C. , Shafer William M. , Swaims-Kohlmeier Alison 
Published: May 2024

The menstrual cycle influences the risk of acquiring sexually transmitted infections (STIs), includingChlamydia trachomatis(C. trachomatis), although the underlying immune contributions are poorly defined. A mouse model simulating the immune-mediated process of menstruation could provide valuable insights into tissue-specific determinants of protection against chlamydial infection within the cervicovaginal and uterine mucosae comprising the female reproductive tract (FRT). Here, we used the pseudopregnancy approach in naïve C57Bl/6 mice and performed vaginal challenge withChlamydia muridarum(C. muridarum) at decidualization, endometrial tissue remodeling, or uterine repair. This strategy identified that the time frame comprising uterine repair correlated with robust infection and greater bacterial burden as compared with mice on hormonal contraception, while challenges during endometrial remodeling were least likely to result in a productive infection. By comparing the infection site at early time points following chlamydial challenge, we found that a greater abundance of innate effector populations and proinflammatory signaling, including IFNψ correlated with protection. FRT immune profiling in uninfected mice over pseudopregnancy or in pig-tailed macaques over the menstrual cycle identified NK cell infiltration into the cervicovaginal tissues and lumen over the course of endometrial remodeling. Notably, NK cell depletion over this time frame reversed protection, with mice now productively infected withC. muridarumfollowing challenge. This study shows that the pseudopregnancy murine menstruation model recapitulates immune changes in the FRT as a result of endometrial remodeling and identifies NK cell localization at the FRT as essential for immune protection against primaryC. muridaruminfection.

Author Summary

Although the vast majority of women and adolescent girls of reproductive age experience menstruation, we have little insight into how this tissue remodeling process alters mucosal immune defenses against infection by genitourinary pathogens. In this study, we used a murine model of menstruation to investigate how endometrial shedding and repair alters the immune landscape in the female reproductive tract (FRT) to influence chlamydial infections. Using this approach, we identified that endometrial remodeling regulates a substantial pro-inflammatory immune response, including NK cell recruitment into the cervicovaginal tissues, and we further confirmed this phenomenon is occurring in a naturally menstruating species. The localization of NK cells in the FRT at the time of challenge was determined to be responsible for rapid immune protection that reducedC. muridarumburden, as experimental depletion of these cells over this timeframe now led to productive infections. Taken together, this study identifies that murine models of menstruation can be a valuable tool for investigating how the menstrual cycle modulates immune homeostasis and for identifying ways to strengthen mucosal immune defenses against genitourinary pathogens in women.