PROJECT SUMMARY/ABSTRACT Infectious gastroenteritis is a leading cause of morbidity and mortality worldwide. Diarrheagenic E. coli (DEC), particularly enteropathogenic (EPEC) and enteroaggregative (EAEC) E. coli, are well established as important causes of gastroenteritis in infants living in low- and middle-income countries (LMICs). Although some observations suggest that adults in LMICs may asymptomatically harbor DEC and that DEC may be a frequent but unappreciated cause of diarrhea in young children in HICs, the contribution of these organisms to gastrointestinal (GI) illness in adults living in high-income countries (HICs) is poorly understood. Multiplex PCR panels enabling rapid detection of the common causes of infectious gastroenteritis, including EPEC/EAEC, were approved by the FDA in 2014, and are increasingly used by clinical laboratories. Recent studies employing multiplex panels indicate that DEC are commonly found in adults in HICs. A multicenter study of patients with gastroenteritis in 10 European countries found that EPEC was the most common pathogen detected. However, EPEC/EAEC were frequently found in samples containing multiple pathogens, raising questions about their clinical significance. In our laboratories at the University of Washington, EPEC and EAEC comprise 22.5% and 12.3% of all positive stool panel results, respectively. In this proposal, I plan to perform both retrospective and prospective studies to better define the clinical significance of EPEC/EAEC in U.S. adults. The specific aims are to: 1) perform a retrospective analysis of the clinical features, risk factors, antimicrobial susceptibility, and outcomes of symptomatic adult patients with stool samples positive for EPEC/EAEC, and 2) create a repository of EPEC/EAEC strains from symptomatic adult patients using prospectively collected residual stool samples and perform whole genome sequencing (WGS) to define the molecular epidemiology of DEC in Seattle adults. These studies will provide new insights into the clinical importance of DEC in HICs and inform strategies for their management and prevention. The research will be supplemented by coursework and specialized training activities as part of a five-year career development plan to allow me to become an independent investigator. Intensive training in next-generation sequencing technologies and bioinformatics with mentoring by experts in the fields of infectious diseases and bacterial genomics will allow me to achieve my long-term objective of becoming a productive independent investigator with a focus on the molecular epidemiology of bacterial infections.