PROJECT SUMMARY Staphylococcus aureus is a bacterial species that causes infections of the skin, lungs, blood and internal organs. These infections can have their onset in the community or in the health care setting, including those caused by antimicrobial-resistant strains called methicillin-resistant S. aureus (MRSA). About 28-50% of all people are asymptomatic carriers of this species on their bodies. The interaction of S. aureus strains in the community and in hospitals has not been adequately studied. While we think that S. aureus can spread from person to person in hospitals, we are not sure how often that happens, if some strains spread more readily than others in the hospital, and how often infections result from the S. aureus bacteria that patients bring with them on their own bodies. Also, it is unclear how important fomites (inanimate objects) or the bodies of healthcare workers (HCWs) are as intermediate carriers in spreading S. aureus from patient to patient in the hospital. This study will be based on data from whole genome sequencing (WGS) of S. aureus collected in two units at the Hospital of the University of Pennsylvania (HUP). For 24 months, we will test all patients upon admission for S. aureus colonization of 4 body sites. For a subset of subjects colonized with S. aureus, we will test fomites in their hospital room for S. aureus. We will choose control patients who are not colonized with S. aureus on admission and test their room fomites to determine what the risk factors are for acquisition and spread of S. aureus in the hospital. Using WGS we will test all of the bacteria causing infections on the study units to see how often specific strains spread, and we will determine whether some genetic traits of S. aureus make them more likely to spread and/or more likely to cause infections. In addition, each month, we will test a sample of the noses and gloves of HCWs on study units to see if they carry S. aureus. We will test common areas of these units to see if fomites carry S. aureus. We will determine if any of the spreading S. aureus strains are found on HCWs or common-area fomites. We will examine all infecting S. aureus isolate genomes from the entire 850-bed HUP during an overlapping 2-year period to identify evidence for distant spread of S. aureus causing an infection. We hope to better understand the genetic markers of virulence and transmissibility in S. aureus. We will test the hypothesis that strains of S. aureus that spread develop a distinct collection of plasmids, which are mobile genetic elements coding for antibiotic resistance or virulence factors that S. aureus may or may not carry. With these results, we may be able to identify patients carrying high-risk S. aureus isolates and develop strategies to prevent the spread of this bacterium in the future.