An innate immune circuit involving the lectin pathway, complement and lung epithelial cells enforce barrier immunity to inhaled fungal disease

The lung mucosal barrier thwarts many inhaled pathogens, including Coccidioides , the causative agent of Valley Fever. Because the earliest stages of pathogen recognition in the lung remain obscure, we investigated the initial events of barrier immunity in a murine model involving inhalation of Coccidioides sp. arthroconidia. Neutrophils accumulated rapidly, within 24 hours, near fungal spores in the bronchiolar airways. This response was driven by pattern recognition via the lectin complement pathway. Bronchiolar club cells propagated C3a signals and amplified the response via convergent C3aR and P2X7 signaling. We identified several MBL2 and P2RX7 polymorphisms that correlated with progressive disease in humans. Our assays revealed that these mutations caused functional impairments in C3a generation and P2X7 responsiveness. Our findings establish how complement signaling and epithelial sensing coordinate early immune responses to fungal infection, offering insights into essential host defense mechanisms and risk factors for disease progression in coccidioidomycosis.