Modeling antiviral immune responses across distinct epithelial niches of the female reproductive tract using organoids 4108

Abstract Description The female reproductive tract (FRT) is a significant entry point for a number of pathogens, and epithelial cells bordering the FRT mucosa are often pathogens’ initial targets during infection. Epithelium-intrinsic innate immune defenses are crucial to limit initial pathogen replication. Epithelial cells also shape local adaptive immunity and are crucial for establishing robust resident memory T cell (TRM)-mediated immunity. However, our understanding of how the FRT epithelium coordinates antiviral defense is far from complete. This issue is further complicated by the distinct epithelial linings across the FRT: single layer columnar epithelia (type-1 mucosa) line the endometrium and endocervix, while stratified squamous epithelia (type-2 mucosa) border the ectocervix and vagina. Here we established three-dimensional organoids resembling type-1 and -2 mucosa that maintained the architectural characteristics of their respective native epithelia and were susceptible to infection by Herpes simplex virus-1/2. We characterized epithelial innate immune responses upon viral infection as well as the interaction of infected epithelium with effector CD8 T cells. This model also allowed testing of functional capabilities of TRM cells against pathogen challenge in distinct mucosal epithelium. Altogether we established a reductionist platform to conduct mechanistic studies of epithelial immunity and epithelial-T cell interactions in the reproductive mucosa. Funding Sources Supported by: NIH R01 AI177704; NIH R21AI183017 Topic Categories Viral Immunology (VIR)