Tuft cells (TCs) act as crucial airway sentinels that detect bacterial metabolites and initiate immune responses, yet the underlying mechanisms remain poorly understood. Here, we identify tracheal TCs as the initial source of leukotrienes (LTs), released during bacterial infection. Tracheal TCs discriminate pathogenic from commensal bacteria by sensing extracellular ATP (eATP) released by pathogens, including Pseudomonas aeruginosa and Rodentibacter pneumotropicus, within 4 h of infection, through the transient receptor potential cation channel subfamily M member 5 (Trpm5). This induces the LT release, including LTB(4), and promotes rapid recruitment of neutrophils and macrophages to the trachea and alveolar spaces. Trpm5(-/-) mice failed to detect bacterial eATP, exhibited neutrophil sequestration in the spleen, and became colonized following R. pneumotropicus infection, while Trpm5(+/+) mice efficiently cleared the pathogen. These findings uncover a critical TC-dependent sensing mechanism in pneumonia, establishing TCs as both ATP sensors and triggers of acute innate immune responses.
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