PROJECT SUMMARYEnteric infections and their associated sequelae, including pain, nausea, inflammation and diarrhea, are majorcauses of morbidity and mortality worldwide, particularly in children. Being at the frontline of intestinal hostdefense, intestinal epithelial cells (IECs) are the frequent target of enteric pathogens. It is generally believedthat during enteric infections, the gut epithelium and overlying mucus layer, which are at the forefront of thehost-microbial interface, primarily provide a physical barrier against invading pathogens, whereas any innateimmune response that occurs within the intestinal mucosa is largely driven by the immune/inflammatory cellsresident in the lamina propria. In contrast, recent studies, including our own, ascribe an unprecedented role forIECs as important players in gut innate immune responses. Together, these studies unequivocally showed thatcanonical and non-canonical inflammasomes in IECs promote host defense and inflammatory responses atearly stages of infection by the model enteric pathogen, Salmonella enterica serovar Typhimurium. Theprimary objective of this application is to define the contribution of IEC inflammasomes to antimicrobial hostdefenses in the gut. Our general hypothesis is that IEC intrinsic inflammasomes coordinate several protectiveand anti-microbial pathways at the gut mucosal surface. Two integrated specific aims are proposed to test thishypothesis. First, we will delineate the protective role of IEC inflammasomes against enteric pathogens in vitroand in vivo, and assess the regulation and temporal contribution of IEC canonical and non-canonicalinflammasomes during infection. Second, we will elucidate goblet cell-specific inflammasome-dependentdefense responses. Completion of this proposal will close a significant knowledge gap regarding the impact ofepithelium-intrinsic inflammasomes on intestinal antimicrobial defense, homeostasis and disease development.