Project Summary/Abstract This grant seeks to understand the interactions between intestinal helminth infection and type 2 immune responses that drive re-modeling of the intestinal epithelial barrier. Although type 2 immunity has been long- associated with adaptive, chronic helminth intestinal infections, host protection is largely ineffective, and worms continue to sustain egg-laying for months to years. The discovery of Group 2 innate lymphoid cells, or ILC2s, by my group and others in 2010, opened new areas of research that uncovered physiologic processes associated with type 2 immune cytokines relevant to metabolic and tissue homeostasis, suggesting the alternative narrative that evolutionarily adapted parasites co-opt integral homeostatic pathways in order to sustain chronic infection, access host nutrients, and preserve tissue integrity necessary to maintain transmission of off-spring. In prior support from this grant, we discovered that tuft cells, rare mucosal epithelial cells, are the source of IL-25, a key cytokine involved in activation of tissue ILC2s to release type 2 cytokines. After intestinal helminth infection, mice activate lamina propria ILC2s to secrete IL-13, which alters progenitor cell fate in intestinal crypts toward secretory cells, particularly tuft cells and goblet cells, thus identifying a critical tuft cell – ILC2 circuit that integrates type 2 immunity with tissue homeostasis. In this renewal, we propose to understand this circuit in order to be able to manipulate it in directions that curtail helminth infection while preserving bowel integrity. The three Specific Aims involve defining the necessity for circuit activation to sustain chronic parasitization; outlining the mechanisms underlying the small intestinal changes in physiology that result from chronic circuit activation; and uncovering endogenous regulatory elements in the circuit that are circumvented by parasites in order to maintain chronic activation of the tuft cell – ILC2 circuit. We believe that understanding these basic pathways has great potential not only for control of parasitic helminthes, but also to impact many diseases of intestinal dysfunction that remain of importance to humans.