Unraveling tuft cell receptors and effector biosynthesis through interactome analysis

Objective

Complex organisms rely on specialized organ structures to interact with their environment, facilitating vital exchanges of molecules. The same structures create vulnerabilities to colonization by microorganisms, requiring sophisticated defense mechanisms. Central to these defenses is the innate immune system's ability to detect and rapidly respond to pathogens through diverse sensor mechanisms. While significant progress has been made in understanding the detection of viruses, bacteria, and fungi, critical gaps remain in how the innate immune system detects large, multicellular parasites like helminths, which pose substantial health challenges to humans and livestock. Tuft cells, rare chemosensory epithelial cells in mucosal epithelia, play a critical role in initiating type 2 immune responses in crosstalk with group 2 innate lymphoid cells. Tuft cells secrete effector molecules such as IL-25, cysteinyl leukotrienes, and acetylcholine, orchestrating defense mechanisms against helminths. While the tuft cell response to microbe-derived succinate is mediated by the GPCR SUCNR1, this pathway is dispensable for helminth detection. Thus, the central questions remain: how do tuft cells sense the presence of helminths, how are these inputs integrated, and how are they converted into distinct effector outputs? This proposal addresses three key objectives: 1) developing innovative tools to track tuft cell activation and effector molecule release; 2) employing orthogonal approaches to identify tuft cell agonist-receptor pairs by combining interactome studies with screens for helminth-derived molecules; and 3) dissecting protein networks controlling distinct tuft cell outputs. By applying cutting-edge methods in innovative ways to mouse and human tuft cells and integrating newly developed tools, this research addresses major gaps in innate immunity. Furthermore, it will serve as a methodological proof-of-concept, enabling future advances in epithelial cell research and beyond.