The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes

Nat Commun. 2018 Oct 15;9(1):4260. doi: 10.1038/s41467-018-06607-1.

Abstract

Clearance of invading microbes requires phagocytes of the innate immune system. However, successful pathogens have evolved sophisticated strategies to evade immune killing. The opportunistic human fungal pathogen Candida albicans is efficiently phagocytosed by macrophages, but causes inflammasome activation, host cytolysis, and escapes after hypha formation. Previous studies suggest that macrophage lysis by C. albicans results from early inflammasome-dependent cell death (pyroptosis), late damage due to glucose depletion and membrane piercing by growing hyphae. Here we show that Candidalysin, a cytolytic peptide toxin encoded by the hypha-associated gene ECE1, is both a central trigger for NLRP3 inflammasome-dependent caspase-1 activation via potassium efflux and a key driver of inflammasome-independent cytolysis of macrophages and dendritic cells upon infection with C. albicans. This suggests that Candidalysin-induced cell damage is a third mechanism of C. albicans-mediated mononuclear phagocyte cell death in addition to damage caused by pyroptosis and the growth of glucose-consuming hyphae.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Caspase 1 / metabolism
  • Cell Death / drug effects
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Female
  • Fungal Proteins / toxicity*
  • Humans
  • Inflammasomes / metabolism*
  • Inflammation / pathology
  • Interleukin-1beta / metabolism
  • Leukocytes, Mononuclear / cytology*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Mycotoxins / toxicity*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Necrosis
  • Phagocytes / cytology*
  • Phagocytes / drug effects
  • Phagocytes / metabolism
  • Phagosomes / drug effects
  • Phagosomes / metabolism
  • Potassium / pharmacology

Substances

  • Actins
  • ECE1 protein, Candida albicans
  • Fungal Proteins
  • Inflammasomes
  • Interleukin-1beta
  • Mycotoxins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Caspase 1
  • Potassium

Grant support