The escape of Candida albicans from macrophages is enabled by the fungal toxin candidalysin and two host cell death pathways

Françios A.B. Olivier, Volker Hilsenstein, Harshini Weerasinghe, Ashley Weir, Sebastian Hughes, Simon Crawford, James E. Vince, Michael J. Hickey, Ana Traven

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)

Abstract

The egress of Candida hyphae from macrophages facilitates immune evasion, but it also alerts macrophages to infection and triggers inflammation. To better define the mechanisms, here we develop an imaging assay to directly and dynamically quantify hyphal escape and correlate it to macrophage responses. The assay reveals that Candida escapes by using two pore-forming proteins to permeabilize macrophage membranes: the fungal toxin candidalysin and Nlrp3 inflammasome-activated Gasdermin D. Candidalysin plays a major role in escape, with Nlrp3 and Gasdermin D-dependent and -independent contributions. The inactivation of Nlrp3 does not reduce hyphal escape, and we identify ETosis via macrophage extracellular trap formation as an additional pathway facilitating hyphal escape. Suppressing hyphal escape does not reduce fungal loads, but it does reduce inflammatory activation. Our findings explain how Candida escapes from macrophages by using three strategies: permeabilizing macrophage membranes via candidalysin and engaging two host cell death pathways, Gasdermin D-mediated pyroptosis and ETosis.

Original languageEnglish
Article number111374
Number of pages25
JournalCell Reports
Volume40
Issue number12
DOIs
Publication statusPublished - 20 Sept 2022

Keywords

  • antifungal inflammation
  • Candida albicans
  • candidalysin
  • CP: Immunology
  • CP: Microbiology
  • fungal pathogen
  • Gasdermin D
  • hyphae
  • hyphal escape
  • inflammasome
  • macrophage
  • NLRP3

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