PROJECT SUMMARY Staphylococcus aureus infection in otherwise healthy adults and children is a significant cause of morbidity, mortality, and economic loss. Recurrence of infection is common, highlighting the fact that S. aureus subverts the development of protective immunity. The development of a vaccine to prevent S. aureus infection has been a premier goal in the field for over two decades, yet multiple human vaccine candidates have failed in clinical trials. Understanding the pathogen and host-specific factors that modulate susceptibility to S. aureus infection is expected to provide insight to advance vaccine design and implementation, but also affords an opportunity to develop specific bedside-accessible tools for objectively assessing individual patient risk. Such tools are required to advance the field toward the goals of personalized and precision medicine. Extensive research, including our own studies, supports the targeting of S. aureus α-toxin (Hla) as a virulence factor to protect against infection. The interaction of Hla with its eukaryotic receptor ADAM10 provides an additional window of opportunity to evaluate whether host-specific factors that modify ADAM10 expression or cellular activity impact susceptibility to S. aureus disease. We have successfully leveraged human clinical studies of S. aureus-infected children and experimental perturbation of ADAM10 in a mouse model system to examine whether a single nucleotide polymorphism (SNP) in the ADAM10 promoter (rs653765) alters susceptibility to S. aureus infection. Two complementary lines of data provide initial insight that this SNP is of functional relevance: 1) children with the rs653765 GG genotype display a significant reduction in odds ratio of invasive S. aureus infection; 2) engineered SNP variants of ADAM10 in novel mouse lines reflect the initial clinical findings observed in humans harboring the rs653765 GG genotype, and suggest that the SNP type influences susceptibility to skin and soft tissue infection. In this project, we propose to leverage existing human genomic DNA biospecimens from an ongoing study of pediatric immunity to S. aureus infection to fully characterize the impact of ADAM10 rs653765 SNP variation in susceptibility to S. aureus infection. We will pair this analysis with hypothesis-driven studies to define the molecular and cellular mechanisms by which the rs653765 SNP alters host susceptibility to disease. These studies which sit at the intersection of human genetic epidemiology and mechanistic research afford a rare opportunity to define a focused biomarker that can inform an understanding of risk for S. aureus disease. The successful completion of these studies would provide an unparalleled opportunity to utilize SNP typing to advance personalized care in the context of infectious disease.