Lawrence Laurel A, Williams Mark Elliott, Vidal Paola, Varughese Richa S, Li Zheng-Rong Tiger, Chen Thien Duy, Roy Melissa A, Tuske Steven C, Lowen Anice C, Scharer Christopher D, Shafer William M, Swaims-Kohlmeier Alison
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Division of Pathology Emory National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
PLoS Pathog. 2025 Jun 6;21(6):e1012276. doi: 10.1371/journal.ppat.1012276. eCollection 2025 Jun.
The menstrual cycle influences the risk of acquiring sexually transmitted infections (STIs), including those caused by the pathogen Chlamydia trachomatis (C. trachomatis). However, the underlying immune contributions are poorly defined. A mouse model simulating the repetitive immune-mediated process of menstruation could provide valuable insights into tissue-specific determinants of protection against chlamydial infection within the cervicovaginal and uterine mucosae of the female reproductive tract (FRT). Here, we used the pseudopregnancy approach for inducing menstruation in naïve C57Bl/6 mice and performed vaginal challenge with Chlamydia muridarum (C. muridarum) over the course of decidualization, endometrial tissue remodeling, and menstruation. This strategy identified that a time point over pseudopregnancy corresponding to the late luteal phase of the menstrual cycle correlated with reduced bacterial burden. By evaluating the early infection site following challenge at this time point, we found that a greater abundance of NK cell populations and proinflammatory signaling, including IFNγ, were strongly correlated with protection. FRT immune profiling in uninfected mice over pseudopregnancy or in pig-tailed macaques over the menstrual cycle identified periodic NK cell infiltration into the cervicovaginal tissues and luminal surface occurring over a similar time frame. Notably, these cell populations were transcriptionally distinct and enriched for programs associated with NK cell effector functions. Depletion of FRT NK cells during the late luteal phase time frame resulted in a loss of protection, enabling productive infection following C. muridarum challenge. This study shows that the pseudopregnancy murine menstruation model recapitulates dynamic changes occurring in mucosal immune states throughout the FRT as a result of endometrial remodeling and identifies NK cell localization at the FRT barrier site of pathogen exposure as essential for immune protection against primary C. muridarum infection.
月经周期会影响获得性传播感染（STIs）的风险，包括由沙眼衣原体（C. trachomatis）病原体引起的感染。然而，其潜在的免疫作用尚不清楚。一个模拟月经重复性免疫介导过程的小鼠模型，可为深入了解女性生殖道（FRT）宫颈阴道和子宫黏膜中针对衣原体感染的组织特异性保护决定因素提供有价值的见解。在此，我们采用假孕方法诱导未接触过病原体的C57Bl/6小鼠月经，并在蜕膜化、子宫内膜组织重塑和月经过程中用鼠衣原体（C. muridarum）进行阴道攻击。该策略确定，假孕过程中与月经周期黄体晚期相对应的时间点与细菌载量降低相关。通过评估此时攻击后的早期感染部位，我们发现大量自然杀伤（NK）细胞群体和包括干扰素γ（IFNγ）在内的促炎信号与保护作用密切相关。对假孕期间未感染小鼠或月经周期中的食蟹猴进行FRT免疫分析发现，在相似的时间范围内，宫颈阴道组织和腔表面会出现周期性NK细胞浸润。值得注意的是，这些细胞群体在转录上是不同的，并且富含与NK细胞效应功能相关的程序。在黄体晚期耗尽FRT中的NK细胞会导致保护作用丧失，使鼠衣原体攻击后能够发生有效感染。这项研究表明，假孕小鼠月经模型概括了由于子宫内膜重塑而在整个FRT黏膜免疫状态中发生的动态变化，并确定NK细胞在病原体暴露的FRT屏障部位的定位对于抵抗原发性鼠衣原体感染的免疫保护至关重要。
