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Candidalysin triggers epithelial cellular stresses that induce necrotic death

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article numbere13371
JournalCellular Microbiology
Early online date3 Jun 2021
DOIs
Accepted/In press1 Jun 2021
E-pub ahead of print3 Jun 2021

Bibliographical note

Funding Information: This work was supported by grants from the Wellcome Trust (214229_Z_18_Z), Biotechnology & Biological Sciences Research Council (BB/N014677/1), National Institutes of Health (R37‐DE022550) and the NIH Research at Guys and St. Thomas's NHS Foundation Trust and the King's College London Biomedical Research Centre (IS‐BRC‐1215‐20006) to Julian R. Naglik. Bernhard Hube was supported by German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) project Hu 528/21‐1 and the Balance of the Microverse Cluster (Germany's Excellence Strategy – EXC 2051 – Project‐ID 390713860). M.M. was the recipient of a Heart and Stroke Pfizer Research Fellowship and is currently supported on Canadian Institutes of Health Research grant FDN‐143202. Funding Information: Biotechnology and Biological Sciences Research Council, Grant/Award Number: BB/N014677/1; National Institutes of Health, Grant/Award Number: R37‐DE022550; Wellcome Trust, Grant/Award Number: 214229_Z_18_Z; Canadian Institutes of Health Research, Grant/Award Number: FDN‐143202; Balance of the Microverse Cluster, Grant/Award Number: 390713860; German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), Grant/Award Number: 528/21‐1; NIH Research at Guys and St. Thomas's NHS Foundation Trust and the King's College London Biomedical Research Centre, Grant/Award Number: IS‐BRC‐1215‐20006 Funding information Publisher Copyright: © 2021 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Candida albicans is a common opportunistic fungal pathogen that causes a wide range of infections from superficial mucosal to hematogenously disseminated candidiasis. The hyphal form plays an important role in the pathogenic process by invading epithelial cells and causing tissue damage. Notably, the secretion of the hyphal toxin candidalysin is essential for both epithelial cell damage and activation of mucosal immune responses. However, the mechanism of candidalysin-induced cell death remains unclear. Here, we examined the induction of cell death by candidalysin in oral epithelial cells. Fluorescent imaging using healthy/apoptotic/necrotic cell markers revealed that candidalysin causes a rapid and marked increase in the population of necrotic rather than apoptotic cells in a concentration dependent manner. Activation of a necrosis-like pathway was confirmed since C. albicans and candidalysin failed to activate caspase-8 and -3, or the cleavage of poly (ADP-ribose) polymerase. Furthermore, oral epithelial cells treated with candidalysin showed rapid production of reactive oxygen species, disruption of mitochondria activity and mitochondrial membrane potential, ATP depletion and cytochrome c release. Collectively, these data demonstrate that oral epithelial cells respond to the secreted fungal toxin candidalysin by triggering numerous cellular stress responses that induce necrotic death.

Take aways
Candidalysin secreted from Candida albicans causes epithelial cell stress.
Candidalysin induces calcium influx and oxidative stress in host cells.
Candidalysin induces mitochondrial dysfunction, ATP depletion and epithelial necrosis.
The toxicity of candidalysin is mediated from the epithelial cell surface.

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