Piezo1 initiates host immune defense against pathogenic fungi through mechanosensory recognition of Candida albicans hyphae

Candida albicans metamorphoses from benign yeast to a rigid hyphae , becoming an opportunistic pathogen in immunocompromised patients. The process by which immune cells discern fungal transformations remains elusive. Here we report that the mechanosensitive ion channel Piezo1 is indispensable for recognizing fungal hyphae and triggering anti-fungal innate immune responses. Hyphae-triggered Piezo1 activation increased CLRs expression in innate immune cells by inducing the expression of C/EBPb via the Piezo1/CaMKs/CREB axis. In addition, Piezo1/CaMKs signaling activated kinases NDR1/2, which augmented NLRP3 inflammasome assembly and promoted hyphae-induced inflammation. Abolishing the yeast-to-hyphae transition dampens CLR and NLRP3 activation. Piezo1-deficient mice exhibit compromised clearance of C. albicans infection, whereas Piezo1 agonist amplifies C. albicans clearance. In addition, CaMKs, CREB or NDR1/2 inhibition exacerbates hyphae infections, like Piezo1 deficiency. Therefore, we ascertain Piezo1-mediated mechanotransduction as vital for immune surveillance and control of hyphal C. albicans, heralding Piezo1 agonist as a potential remedy for fungal infections. Overall design: RNA-seq analysis of WT and Piezo1KO BMDMs, with or without YODA1 treatment.