PROJECT SUMMARY Staphylococcus aureus is a common cause of bacterial infections in the United States (US), including skin and soft tissue infections and invasive infections (e.g., sepsis, pneumonia and necrotizing fasciitis). Carriage of S. aureus is an established risk factor for infection. Despite observed carriage prevalence similar to that in the general United States population, Indigenous populations experience a disproportionate burden of S. aureus disease, largely due to disparities in the social determinants of health. Decolonization can be achieved using a variety of regimens, each of which has requirements that could be challenging in under-resourced settings. In addition, people are often re-colonized after one-time decolonization and recurrent infections are common. Existing strategies have not been sufficient to control disease and a better understanding of the epidemiology of S. aureus carriage is needed so that effective and feasible approaches to decolonization can be developed. This proposal builds on a long-standing partnership between the Johns Hopkins Center for Indigenous Health, the White Mountain Apache Tribe and the Indian Health Service to produce infectious disease and behavior change interventions that have been scaled across Indigenous populations and the world. We are currently evaluating a community-informed and novel approach to achieve long-term carriage suppression using a combined education and sustained biomedical intervention in the W hite Mountain Apache community in work funded through the Native American Research Centers for Health Program. In this proposal, we will expand this work to answer key outstanding questions about S. aureus epidemiology. Within the context of the trial, we will: 1) evaluate S. aureus genomic diversity within households at the baseline visit by characterizing stored samples collected from individuals, indoor pets, and surfaces within households; 2) evaluate S. aureus transmission dynamics and reservoirs of carriage within households by recruiting and following a subset of households in the trial for four months and testing samples collected from individuals, indoor pets, and surfaces at each visit; and 3) assess reacquisition of S. aureus among individuals receiving a carriage suppression regimen in the trial by characterizing stored samples from each visit. This work will generate critical preliminary data that will inform the design and evaluation of decolonization interventions to be implemented in similarly under-resourced and burdened communities.