Assessing the impact of the vaginal microbiome on reproductive immunity using human ectocervical organoids 3995

Abstract Description Dysbiotic vaginal microbiome is a principal contributor to increased acquisition of several sexually transmitted infections (STIs) in women. Microbial dysbiosis, marked by a shift in microbial composition toward anaerobic species associated with bacterial vaginosis (BV), can compromise the integrity of the genital epithelium. Local immune cells can further foment this inflammation. However, a molecular understanding of how the microbial-immune-epithelial interactions are regulated is lacking. One major hurdle hindering progress is the lack of suitable in vitro models that accurately replicate the complex and dynamic nature of the in vivo vaginal microenvironment. Here, we have established a human cervical epithelial organoid-based system that can serve as a scaffold to integrate immune cells and microbiome-derived signals to better model the reproductive mucosa. Architecturally, these organoids maintained the stratified structure of the ectocervical epithelium. In response to bacterial metabolites derived from a BV-associated microbe Gardnerella vaginalis, these organoids produced pro-inflammatory cytokines that include IL-1β and TNF-α whereas Lactobacillus crispatus-derived bacterial supernatant didn’t alter these cytokine levels. Introducing immune cells in these organoids will enable mechanistic interrogation of the tripartite interaction among the microbiome, immune cells, and epithelium underlying BV-associated epithelial disruption and consequent susceptibility to STIs. Funding Sources Supported by NIH R01AI177704; NIH R21AI183017 Topic Categories Mucosal and Regional Immunology (MUC)