1. Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages
- Author
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Hongbo Yu, Fei Liu, Hiroto Kambara, Xuemei Xie, Maikel Acosta-Zaldívar, Cunling Zhang, Julia R. Köhler, Jiajia Li, Hongbo R. Luo, Rongxia Guo, Ning-Ning Liu, Ting Bei, Fengxia Ma, Li Zhao, Xionghui Ding, Wenli Han, Xiaoyu Zhang, Wanjun Qi, and Apurva Kanneganti
- Subjects
Programmed cell death ,Inflammasomes ,Science ,Interleukin-1beta ,General Physics and Astronomy ,Kaplan-Meier Estimate ,Kidney ,Article ,General Biochemistry, Genetics and Molecular Biology ,Microbiology ,Sepsis ,Mediator ,Candida albicans ,medicine ,Animals ,Humans ,Cells, Cultured ,Mice, Knockout ,Multidisciplinary ,biology ,Immune cell death ,Macrophages ,Caspase 1 ,Candidiasis ,Intracellular Signaling Peptides and Proteins ,Pyroptosis ,Inflammasome ,General Chemistry ,Phosphate-Binding Proteins ,medicine.disease ,biology.organism_classification ,Corpus albicans ,Mice, Inbred C57BL ,Host-Pathogen Interactions ,Female ,Infection ,Candidalysin ,medicine.drug - 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., 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.
- Published
- 2021