The impact of aging on neutrophil-mediated protection and inflammation in the female genital mucosa

PROJECT SUMMARY Urogenital infections, including sexually transmitted infections and other genitourinary tract infections, are a major source of morbidity and mortality in older women, yet how aging impacts mucosal immune protection in the female genital tract (FGT) remains largely unknown. Thus, to enable the development of preventive

approaches effective in younger and older women, it is critical to identify the early mucosal mechanisms that confer protection from infection in the FGT and learn how aging alters these protective mechanisms. Neutrophils are key cells for first-line innate protection and are involved in responses to genital infections,

including bacterial, fungal, and viral pathogens. Neutrophils are also involved in physiological reproductive functions and are the first-responder cells to sites of injury to initiate the wound healing process. While the presence of other immune cell types declines with age in the FGT, neutrophils remain constant. However, despite

neutrophils’ critical role in innate protection and tissue homeostasis, and their continual presence in the FGT with age, the extent to which aging impacts FGT neutrophil-mediated protection against infection or tissue inflammation as women age is unknown. The PI’s research group recently discovered that, despite neutrophil presence in the FGT of older women, their

antiviral responses are compromised. Using novel multi-omics technologies, they have identified different subsets of neutrophils with defense and homeostatic functions, and defined neutrophil intra-tissue spatial location and transcriptional profiles in younger women. Building on these preliminary results, the central

hypothesis is that aging modifies tissue distribution and function of specific neutrophil subsets, leading to decreased neutrophil-mediated mucosal protection and increased tissue inflammation in the FGT as women age. Using human hysterectomy samples from endometrium, endocervix, and ectocervix from younger and older

women, this project will combine multi-omics single-cell sequencing approaches, tissue spatial transcriptomics, and in vitro functional assays of genital neutrophils to define how aging modifies neutrophil defense and homeostatic functions, tissue distribution, and their contribution to first-line mucosal protection.

It is expected that these studies will define, for the first time, the mechanisms responsible for neutrophil-mediated protection in the FGT and how they are modified with aging. The identification of an inducible/modifiable form of innate protection in the FGT and how aging modifies this protection will have a positive translational impact,

enabling the development of novel strategies for protection against sexually-transmitted infections and other genitourinary tract infections in older women, a group that is generally excluded from STI prevention research.