DESCRIPTION (provided by the applicant): The majority of infections occur via mucosal surfaces, either through breaks in the mucosal barrier or through a pathogen's ability to evade the "front lines" of mucosal defense, the innate immune barrier defenses. Innate defenses prevent the majority of bacteria from damaging or crossing the mucosa, and are integral in signaling the host when this barrier has been breached. Antimicrobial peptides are important components of the mucosal barrier defense. In the small intestinal crypts, highly secretory Paneth cells are the primary source of antimicrobial peptides and other effector molecules. These peptides have demonstrated broad-spectrum antibiotic activity in vitro, and recently have been shown to have a significant role in host defense in vivo. Using Salmonella enterica serovar Typhimurium as a model pathogen we will study Paneth cell (PC) effector response to bacterial infection and the impact of this response on the innate protection of the host. We have found that oral wild type S. typhimurium infection of the mouse results in persistent bacterial colonization of the small intestine, decreased expression and production of PC cryptdins and lysozyme, and alteration of the commensal microbiota. We hypothesize that Paneth cell effector expression can be down-regulated by bacterial infection, and that the subsequent decreases in PC effectors result in changes in the composition of the commensal microbiota and prolonged pathogen colonization. Aim 1 will focus on the physiologic mechanisms of PC effector regulation, using specific Salmonella mutants to identify the role of different routes of host-pathogen interaction and the requirement for specific Salmonella pathogenicity island 1 and 2 effectors. Aim 2 will focus on the biological implications of PC effector reduction with respect to persistent pathogen colonization and impact on the commensal microbiota. The proposed studies should provide greater understanding of the physiologic mechanism of PC effector regulation, the role of PC effectors in innate mucosal host defense, and the interplay between host and pathogen that determine the balance between successful pathogenesis and host survival.