Project Summary Epithelial cells form a physical and biochemical barrier against the vast number of microbes inhabiting the gut. Secretion of mucus and antimicrobial peptides by epithelial cells enhance barrier function and shape the composition of the microbiota. Intestinal epithelial cells also monitor lumenal microbes and transmit information to underlying immune cells to shape mucosal immunity. Within the collective epithelium there are six specialized subsets of cells, including tuft cells. Previously, the function of tuft cells was unknown until our group and two others reported their role in parasite response and mucosal immunity. The mechanistic basis of parasite recognition by tuft cells is poorly understood, as both the receptors and microbial agonists are unknown. To close this knowledge gap, this proposal will build on our observation that tuft cells utilize taste-chemosensation to respond to parasite infections. First, we will identify the taste-chemosensory receptors that detect parasites. In parallel we determine the microbial agonists that stimulate tuft cell taste chemosensation. Using next-generation sequencing and gnotobiotic mice, this study will disentangle the role of the parasite-altered microbiome from direct stimulation of tuft cells by parasites and their products. This project will yield valuable information on specific interactions between tuft cell receptors and their agonists thereby expanding the understanding of taste receptors as novel intestinal microbial recognition receptors. Tuft cells and taste-chemosensation are fundamentally new form of microbial detection in the gut and represent a promising area to develop future therapies targeting intestinal inflammatory disease. In addition the data, training, and knowledge obtained from this proposal are critical for my continued development as an independent investigator.