The Role of Immune Senescence in Reducing Neutrophil-Mediated Protection in The Female Genital Tract 4407

Abstract Description Susceptibility to sexually transmitted infections increases with age, however the innate mechanisms that protect against genital infections and how they change with age remain undefined. Neutrophils, the most abundant innate immune cells in the genital mucosa, serve as first-responders to injury and infection. We previously reported impaired neutrophil responses to HIV with age, though the underlying mechanisms remain unknown. We hypothesize with aging, the genital mucosa becomes senescent resulting in an altered tissue-associated neutrophil profile and impaired function. Three subsets of genital neutrophils were identified at homeostasis (CD15hi,CD15lo,CD66blo). CD15hi neutrophils were enriched for maturation markers, and CD15lo preferentially expressed CXCR4, a neutrophil aging marker. Confocal imaging showed tissue-specific distribution of neutrophils at homeostasis. Endometrial neutrophils aggregated inside glands but were enriched at the luminal epithelium in endocervix and ectocervix. Bulk RNA sequencing of the epithelial/stromal fraction identified 119 genes significantly correlated to age. Pathway analysis revealed increased signatures cellular senescence. Distinct neutrophil subsets populate the genital mucosa in a tissue-specific, spatially organized manner. With age, genital tissues undergo transcriptional changes consistent with tissue senescence. Future studies will determine how tissue senescence influences neutrophil function and mucosal protection. Funding Sources U01AG084766; NIH-R01AG060801; NIH-R21AI172065; Burroughs Welcome Fund; Investigators in the Pathogenesis of Infectious Disease Topic Categories Mucosal and Regional Immunology (MUC)