Allergen and damage sensing by chemosensory tuft cells in the airway

About This Grant

PROJECT SUMMARY: Airway chemosensory tuft cells are specialized epithelial cells strategically positioned at the apical epithelial surface in the nose and trachea at the first site of interaction with the inhaled air. We previously established that nasal tuft cells are direct sensors of allergens and the danger molecules ATP and UTP and generate cysteinyl leukotrienes and prostaglandins upon allergen and ATP activation. Genetic deletion of tuft cells and tuft cell-derived cysteinyl leukotrienes leads to reduced nasal and lung inflammation. Although tuft cells are quite abundant in the nose, they are rare in the trachea and almost completely absent in the naïve lung. Our central hypothesis is that tuft cells act as central distribution hubs of epithelial activation after allergen and pathogen inhalation, directing local nasal inflammation and a nose-to-lung axis through the engagement of nociceptors. The overall goal of this proposal is to define how tuft cells propagate activation signals locally and how they engage nociceptors to direct inflammation in the lung where their numbers are limited. In Aim 1, we will define distinct ligand-receptor pairs relevant to allergen and danger sensing in the three distinct subsets of airway tuft cells. We will use a combination of calcium imaging in whole tissue explants with in vitro stimulation of co-cultures of tuft cells and ionocytes, along with mediator assessment. In Aim 2, we will dissect the local tissue inflammatory and remodeling pathways driven by tuft cells and interrogate the nose to lung communication pathways. Results from the proposed experiments will provide critical insights into how protective airway responses can be diverted to initiate and propagate inflammation and remodeling, leading to chronic airway diseases.