Pre‐existing mycobacterial infection modulates Candida albicans‐driven pyroptosis

Active tuberculosis patients are at high risk of coinfection with opportunistic fungal pathogen Candida albicans . However, the molecular mechanisms that orchestrate pathogenesis of Mycobacterium tuberculosis (Mtb)‐ C . albicans coinfection remain elusive. In the current study, we utilize a mouse model to demonstrate that Mtb promotes a macrophage environment that is conducive for C . albicans survival. Mtb‐dependent protein kinase Cζ‐WNT signalling axis induces expression of an E3 ubiquitin ligase, constitutive photomorphogenesis protein 1 (COP1). A secondary infection of C . albicans in such Mtb‐infected macrophages causes COP1 to mediate the proteasomal degradation of interferon regulatory factor 9 (IRF9), a cardinal factor that we identified to arbitrate an inflammatory programmed cell death, pyroptosis. In vivo experiments mimicking a pre‐existing Mtb infection demonstrate that inhibition of pyroptosis in mice results in increased C . albicans burden and aberrant lung tissue architecture, leading to increased host mortality. Together, our study reveals the crucial role of pyroptosis regulation for manifesting a successful C . albicans –Mtb coinfection.