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

• Published in: Nature communications 2021-11, Vol.12 (1), p.6699-6699, Article 6699
• Main Authors: Ding, Xionghui, Kambara, Hiroto, Guo, Rongxia, Kanneganti, Apurva, Acosta-Zaldívar, Maikel, Li, Jiajia, Liu, Fei, Bei, Ting, Qi, Wanjun, Xie, Xuemei, Han, Wenli, Liu, Ningning, Zhang, Cunling, Zhang, Xiaoyu, Yu, Hongbo, Zhao, Li, Ma, Fengxia, Köhler, Julia R., Luo, Hongbo R.
• Format: Article
• Language: English
• Subjects: 13/2; 13/31; 14/63; 631/250/1932; 631/250/254; 64/60; 82/51; 96; 96/21; Animals; Candida; Candida albicans; Candida albicans - immunology; Candida albicans - physiology; Candidiasis; Candidiasis - genetics; Candidiasis - immunology; Candidiasis - microbiology; Caspase 1 - genetics; Caspase 1 - immunology; Caspase 1 - metabolism; Cell death; Cells, Cultured; Female; Fungi; Fungicides; Host-Pathogen Interactions - immunology; Humanities and Social Sciences; Humans; Hyphae; IL-1β; Infections; Inflammasomes; Inflammasomes - genetics; Inflammasomes - immunology; Inflammasomes - metabolism; Inhibitors; Interleukin-1beta - immunology; Interleukin-1beta - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - immunology; Intracellular Signaling Peptides and Proteins - metabolism; Kaplan-Meier Estimate; Kidney - immunology; Kidney - metabolism; Kidney - microbiology; Lipopolysaccharides; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Phosphate-Binding Proteins - genetics; Phosphate-Binding Proteins - immunology; Phosphate-Binding Proteins - metabolism; Pore formation; Pyroptosis; Science; Science (multidisciplinary); Sepsis; Signaling; Therapeutic targets; Toxins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27034-9

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. Inflammasome signalling has been shown to protect Candida albicans during infection and as such limits inflammasome inhibitors in this context. Here the authors implicate Gasdermin D in C.ablicans immune evasion and suggests its targeting therapeutically.