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

Lydia Kasper; Annika König; Paul-albert Koenig; Mark S. Gresnigt; Johannes Westman; Rebecca A. Drummond; Michail S. Lionakis; Olaf Groß; Jürgen Ruland; Julian R. Naglik; Bernhard Hube

doi:10.1038/s41467-018-06607-1

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

Lydia Kasper, Annika König, Paul-albert Koenig, Mark S. Gresnigt, Johannes Westman, Rebecca A. Drummond, Michail S. Lionakis, Olaf Groß, Jürgen Ruland, Julian R. Naglik, Bernhard Hube

Centre for Host Microbiome Interactions

Research output: Contribution to journal › Article › peer-review

220 Citations (Scopus)

394 Downloads (Pure)

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.

Original language	English
Article number	4260
Journal	Nature Communications
Volume	9
Issue number	1
Early online date	15 Oct 2018
DOIs	https://doi.org/10.1038/s41467-018-06607-1
Publication status	Published - 31 Dec 2018

Access to Document

10.1038/s41467-018-06607-1Licence: CC BY

The fungal peptide toxin_KASPER_Accepted15September2018Publishedonline15October2018_GOLD VoR (CC BY)Final published version, 4.06 MBLicence: CC BY

Cite this

@article{3e5a681172a04bc9bcd83624d8f30577,

title = "The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes",

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.",

author = "Lydia Kasper and Annika K{\"o}nig and Paul-albert Koenig and Gresnigt, {Mark S.} and Johannes Westman and Drummond, {Rebecca A.} and Lionakis, {Michail S.} and Olaf Gro{\ss} and J{\"u}rgen Ruland and Naglik, {Julian R.} and Bernhard Hube",

year = "2018",

month = dec,

day = "31",

doi = "10.1038/s41467-018-06607-1",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes

AU - Kasper, Lydia

AU - König, Annika

AU - Koenig, Paul-albert

AU - Gresnigt, Mark S.

AU - Westman, Johannes

AU - Drummond, Rebecca A.

AU - Lionakis, Michail S.

AU - Groß, Olaf

AU - Ruland, Jürgen

AU - Naglik, Julian R.

AU - Hube, Bernhard

PY - 2018/12/31

Y1 - 2018/12/31

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-018-06607-1

DO - 10.1038/s41467-018-06607-1

M3 - Article

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4260

ER -

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

Abstract

Access to Document

Fingerprint

Cite this