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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.

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Topic(s)

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2025-COG

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Host institution

UNIVERSITAT ZURICH
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 2 109 411,00
Address
RAMISTRASSE 71
8006 Zurich
Switzerland

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Region
Schweiz/Suisse/Svizzera Zürich Zürich
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 2 109 411,00

Beneficiaries (1)

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