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

Nat Commun. 2021 Nov 18;12(1):6699. doi: 10.1038/s41467-021-27034-9.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Candida albicans / immunology*
  • Candida albicans / physiology
  • Candidiasis / genetics
  • Candidiasis / immunology*
  • Candidiasis / microbiology
  • Caspase 1 / genetics
  • Caspase 1 / immunology
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Female
  • Host-Pathogen Interactions / immunology
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • 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
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphate-Binding Proteins / genetics
  • Phosphate-Binding Proteins / immunology*
  • Phosphate-Binding Proteins / metabolism

Substances

  • Gsdmd protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Phosphate-Binding Proteins
  • Caspase 1