Project summary Infectious diarrhea remains a leading cause of morbidity and mortality in children and immunocompromised patients worldwide. However, the lack of neonatal and immunodeficient animal models that closely mirror human infection in these highly susceptible patient groups has limited our understanding of the disease. Therefore, we propose here the use of novel neonatal and immunodeficient mouse models of disease to study the mechanisms of pathogenesis and host immunity during enteric and systemic infection by the pathogens Citrobacter rodentium and Salmonella enterica serovar Typhimurium. Our first hypothesis is that C. rodentium employs different virulence factors to induce lethal systemic infection in neonatal mice compared to those required for initial intestinal colonization. Specific Aim 1 was designed to identify and characterize significant pathogen factors required for the establishment of bacteremia in neonates using genome-wide screens and functional studies in vivo (1A-C). Specific Aim 2 will address our second hypothesis regarding the protective role of IgG against enteric disease both in the neonatal and adult gut, and the existence of compensatory or alternative mechanisms of pathogen eradication in the absence of IgG (2A-C). Findings obtained with C. rodentium will be tested in the human pathogen S. Typhimurium to allow a broader understanding of the general and specific aspects of microbial pathogenesis and host immunity during infection in susceptible individuals (1D & 2D). These studies have high clinical significance as they may provide novel insight into the pathogenesis of enteric and systemic disease both in children and patients with impaired adaptive immunity, which aligns well with the goals of the National Institute of Allergy and Infectious Diseases (NIAID). Additionally, we have also developed a robust and comprehensive career development and training plan that will provide scientific training in alternative models of infection, mucosal and adaptive immunity, pathology and disease progression, high-throughput data analysis, and state-of-the-art technologies to assess cell state and inflammatory environment in the gut. This plan will also develop and strengthen key professional skills essential to successfully lead an independent research program, including training in mentoring and teaching, scientific communication, networking, grant preparation, and laboratory management. A group of highly qualified and renowned scientists will guide and evaluate the applicant’s efforts to achieve his scientific and career goals. Altogether, the research and career development activities outlined in this proposal, along with the outstanding institutional environment at the University of Michigan, will fully prepare the PI to pursue an independent career in health-oriented research, positioning him as a strong junior faculty in the fields of bacterial pathogenesis, host immunity and host-pathogen interactions.