Grant: Project Grant

Sepsis is a life-threatening illness caused by a dysregulated response to infection, which is associated with 25-30% mortality, and accounts for 1 in 5 deaths globally. It has been known for decades that clinical outcomes in sepsis are different between males and females - with males having a higher incidence, higher illness severity, and higher mortality compared to females in both human studies and animal models. Yet, the underlying mechanisms and treatment implications of sex-biased sepsis pathogenesis have been almost entirely neglected to date. This is in large part because our foundational understanding of sepsis pathogenesis is largely derived from animal studies that included only male subjects. Therefore, it is possible that inappropriate generalization of mechanisms that are only relevant to males may contribute to why, to date, there remains no targeted treatments for sepsis despite many "effective" therapeutic discoveries in (male) animal models. The objective of our research is to address this critical knowledge gap by determining the cellular and molecular mechanisms underlying the male sex bias in sepsis severity and outcomes. In addition, we will translate this new knowledge into therapeutic approaches that address sex-dependent mechanisms of disease. Using a combination of transgenic mice, germ-free mice, and advanced metabolic and immunologic assays, we will dissect the roles of sex chromosomes, hormones, and the microbiome towards mechanisms of sex-dependent pathogenesis in sepsis, and perform translational experiments to incorporate these findings into novel treatment strategies.