Ecological and epithelial regulation of immunity in the female reproductive tract

Abstract

Among mucosal tissues, the female reproductive tract has a unique biological susceptibility to viral infection, as tissue-specific immunity requires rapid antimicrobial responses to pathogens, while maintaining tolerance toward commensal organisms, sperm, and fetal products. Over the last twenty-plus years, a number of research groups have demonstrated two factors that significantly alter the likelihood of acquiring a sexually transmitted infection by the vaginal route: (a) the composition of the vaginal microbiome and (b) the predominant hormone in the days leading up to the encounter. We chose to focus first on women diagnosed with bacterial vaginosis. Because new treatments have not entered the market in decades, it is important that we learn to identify patients likely to experience treatment failure; no criteria currently exist. In our search to identify community signatures associated with treatment failure, we demonstrate that pre-treatment richness and evenness were significantly lower for women who sustained clearance, and that these women also experienced improved mucosal tissue health. We next sought to identify factors that make the vagina an opportune niche for pathogens such as Zika virus. Our findings suggest that in conjunction with a rapid antiviral response, the vaginal epithelium induced a non-canonical "activation" of epithelial cells demonstrated by acute upregulation of genes that function in terminal differentiation and desquamation, in an apparent attempt to increase cell turnover and expel virus. These findings led us to investigate the potential breadth of this response. Through re-analysis of publicly available data from the Gene expression omnibus (GEO), we found that this activation could be broadly observed following TLR stimulation by several TLR ligands, suggesting that this mechanism is a conserved epithelial response to PAMP. Given the essential role of sex hormones in determining immune responses of the FRT, we sought to explore epithelial activation through additional in vivo studies of ovariectomized mice under specific hormone conditions. Analysis via flow cytometry and single-cell RNAseq demonstrated that high levels of progesterone and estrogen – as observed during pregnancy - direct epithelial programs in the vagina to restrain T cell activation and recruitment, subsequently exacerbating infection.