Dual activation of NLRP3 and pyrin inflammasomes mediates host responses to the human fungal pathogen Coccidioides.

Coccidioides is a dimorphic fungal pathogen that grows as a mold in soil and produces infectious arthroconidia. Inhaled arthroconidia transition to spherules containing endospores in mammalian hosts. How distinct developmental forms of Coccidioides interact with immune cells remains poorly defined. Here, we show that arthroconidia activates TLR2 and induces NLRP3-pyrin inflammasomes in macrophages, while ferroptotic signaling promotes arthroconidia killing. Upon transition to spherules, only ruptured spherules-not intact ones-trigger IL-1β production through NLRP3-pyrin inflammasomes and GSDMD-GSDME pores. A TLR2-NLRP3-pyrin-IL-18 axis in macrophages promotes spherule growth. Endospores activate NLRP3 but not pyrin inflammasomes. Caspase-1-deficient mice show improved disease tolerance to coccidioidomycosis despite equivalent fungal burdens, correlating with enhanced neutrophil extracellular trap formation in lung granulomas. Neutrophils respond to spherules through NLRP3-pyrin inflammasomes, GSDMD-GSDME, and MLKL. Together, these findings reveal that Coccidioides morphotypes elicit distinct yet overlapping immune programs, coordinating inflammasome activation and regulated cell death to shape host-pathogen dynamics.