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Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages.

Nature communications (2021-11-20)
Xionghui Ding, Hiroto Kambara, Rongxia Guo, Apurva Kanneganti, Maikel Acosta-Zaldívar, Jiajia Li, Fei Liu, Ting Bei, Wanjun Qi, Xuemei Xie, Wenli Han, Ningning Liu, Cunling Zhang, Xiaoyu Zhang, Hongbo Yu, Li Zhao, Fengxia Ma, Julia R Köhler, Hongbo R Luo
ABSTRACT

Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida-infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida's escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans-induced sepsis.

MATERIALS
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Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, purified immunoglobulin, buffered aqueous solution
Millipore
MILLIPLEX® Mouse High Sensitivity T Cell Panel - Immunology Multiplex Assay, Simultaneous analyze low levels of cytokine and chemokine biomarker with the High Sensitivity Bead-Based Multiplex Assays using the Luminex technology, in mouse serum, plasma and cell culture samples.