Antigen Presenting Cells Link the Female Genital Tract Microbiome to Mucosal Inflammation, With Hormonal Contraception as an Additional Modulator of Inflammatory Signatures

Abstract

The microbiome of the female genital tract (FGT) is closely linked to reproductive health outcomes. Diverse, anaerobe-dominated communities with low Lactobacillus abundance are associated with a number of adverse reproductive outcomes, such as preterm birth, cervical dysplasia, and sexually transmitted infections (STIs), including HIV. Vaginal dysbiosis is associated with local mucosal inflammation, which likely serves as a biological mediator of poor reproductive outcomes. Yet the precise mechanisms of this FGT inflammation remain unclear. Studies in humans have been complicated by confounding demographic, behavioral, and clinical variables. Specifically, hormonal contraception is associated both with changes in the vaginal microbiome and with mucosal inflammation. In this study, we examined the transcriptional landscape of cervical cell populations in a cohort of South African women with differing vaginal microbial community types. We also investigate effects of reproductive hormones on the transcriptional profiles of cervical cells, focusing on the contraceptive depot medroxyprogesterone acetate (DMPA), the most common form of contraception in sub-Saharan Africa. We found that antigen presenting cells (APCs) are key mediators of microbiome associated FGT inflammation. We also found that DMPA is associated with significant transcriptional changes across multiple cell lineages, with some shared and some distinct pathways compared to the inflammatory signature seen with dysbiosis. These results highlight the importance of an integrated, systems-level approach to understanding host-microbe interactions, with an appreciation for important variables, such as reproductive hormones, in the complex system of the FGT mucosa.

Keywords: HIV; female genital tract; hormonal contraception; host-microbiome interaction; inflammation; microbiome; mucosal immunology.

Figure 1

FGT microbiota of the 30 participants included in the analysis. (A) Bar plot representation of the microbial taxa present in the FGT in all participants, grouped by CT. Nugent score was also calculated for 28 of the 30 participants and is represented at the base of the bar plot. (B) Principal coordinates analysis of FGT microbial taxa from the 30 participants.

Figure 2

APC (A, B), epithelial cell (C, D) and CD4+ T cell (E, F) differential gene expression between CTs 3/4 and 1/2 visualized through volcano plots (A, C, E) and significantly enriched gene sets by GSEA using Hallmark gene sets (at FDR-corrected q value of 0.1) based on Hallmark gene lists (B, D, F).

Figure 3

Association of DMPA with FGT APC (A–C), epithelial cell (D–F), and CD4+ T cell (G–I) transcriptional landscape. (A, D, G) Volcano plots showing differentially expressed genes, with significantly differentially expressed genes (BH-corrected p-value of 0.1) shown in darker points. (B, E, H) Significantly enriched gene sets through GSEA based on the Hallmark gene set with an FDR-corrected q-value <0.1. (C, F, I) Significantly differentially expressed genes are shown in heatmaps, with clustering based on Spearman distances.