PROJECT SUMMARYDisease transmission is a multifaceted process mediated by the interactions between the pathogen and host.Salmonella enterica serovars are important human pathogens that cause disease ranging from self-limitinggastroenteritis to persistent systemic infections, such as typhoid fever. Transmission occurs via the fecal-oralroute, and epidemiological analyses have revealed heterogeneity in host transmission capabilities. However,relatively little is known about the factors that dictate pathogen shedding and transmission. A number ofstudies have described mechanisms of Salmonella enterica serovar Typhimurium expansion in micepostantibiotic treatment. However, these mechanisms have not been explored in the absence of antibiotictreatment. Although antibiotic treatment in humans enhances susceptibility to enteric pathogens such as S.Typhimurium and Clostridium difficile, Salmonella colonizes the gut in the absence of antibiotic treatment.Thus, it is important to study the mechanisms of S. Typhimurium emergence and expansion in non-antibiotictreated hosts. We use a mouse model to study molecular mechanisms of S. Typhimurium expansion in themammalian gut in which ~20-30% of these mice shed ?108 CFU/g feces and readily transmit to nave cagemates. We hypothesized that alterations in the diet could influence pathogen shedding. To test this, we fedmice a high cholesterol diet at the time of infection. We have preliminary data demonstrating that highcholesterol diet increases S. Typhimurium shedding levels very rapidly. The long-term goal of this researchproposal is to understand how S. Typhimurium usurps and manipulates the gut microbiome and host immuneresponses during colonization of the mammalian gut. In Aim 1, we will identify host factors that promotecholesterol-dependent expansion of Salmonella in the distal gut. In Aim 2, we will identify and characterizeSalmonella factors required for expansion in the distal gut, and determine whether they are specific forexpansion in mice fed a high cholesterol diet. These studies are aimed at gaining a better understanding of themolecular mechanisms of host-pathogen interactions during S. Typhimurium infections in the gut, andinfluence pathogen transmission. The expected results will lead to new methods of transmission control and tothe rational design of therapeutics that will benefit public health.