Pre‐existing mycobacterial infection modulates Candida albicans‐driven pyroptosis

• Published in: The FEBS journal Vol. 289; no. 6; pp. 1536 - 1551
• Main Authors: Bhatt, Bharat, Prakhar, Praveen, Lohia, Gaurav Kumar, Rajmani, Raju S., Balaji, Kithiganahalli Narayanaswamy
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2022
• Subjects: Animals; Apoptosis; Arbitration; Biodegradation; C. albicans; Candida albicans; Candida albicans - genetics; Cell death; Coinfection; COP1; Humans; Infections; Inflammation; Interferon; Interferon regulatory factor; IRF9; Kinases; M. tuberculosis; Macrophages; Macrophages - metabolism; Mice; Mimicry; Molecular modelling; Mycobacterium tuberculosis; Opportunist infection; Pathogenesis; Photomorphogenesis; Proteasomes; Protein kinase; Protein kinase C; Proteins; Pyroptosis; Secondary infection; Tuberculosis; Ubiquitin; Ubiquitin-protein ligase; ubiquitination; Wnt protein; M. tuberculosis; pyroptosis; COP1; C. albicans; ubiquitination; IRF9
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16243

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. Co‐infection with the opportunistic fungal pathogen Candida albicans commonly occurs in tuberculosis (Mycobacterium tuberculosis, Mtb) patients. In this study, Bhatt et al. established a mouse model to explore the immune and signalling dynamics of co‐infection with Mtb and C. albicans. They show that Candida infection induces pyroptosis in an IRF9‐dependent manner, and this is modulated by pre‐existing Mtb infection, as follows: Mtb‐driven PKCζ‐WNT signalling induces the expression of E3 ubiquitin ligase COP1, which mediates the proteasomal degradation of IRF9. Collectively, their findings indicate that pyroptosis regulation plays a key role in exacerbating the pathogenesis of C. albicans during active tuberculosis.