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

Author

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  • Lydia Kasper

    (Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute)

  • Annika König

    (Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute)

  • Paul-Albert Koenig

    (Technical University of Munich)

  • Mark S. Gresnigt

    (Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute)

  • Johannes Westman

    (The Hospital for Sick Children)

  • Rebecca A. Drummond

    (National Institutes of Health, Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology
    University of Birmingham)

  • Michail S. Lionakis

    (National Institutes of Health, Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology)

  • Olaf Groß

    (University of Freiburg)

  • Jürgen Ruland

    (Technical University of Munich
    Technische Universität München
    German Cancer Consortium (DKTK)
    German Center for Infection Research (DZIF))

  • Julian R. Naglik

    (King’s College London Dental Institute)

  • Bernhard Hube

    (Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute
    Friedrich Schiller University)

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.

Suggested Citation

  • 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, 2018. "The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes," Nature Communications, Nature, vol. 9(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06607-1
    DOI: 10.1038/s41467-018-06607-1
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    Cited by:

    1. Tingting Zhou & Norma V. Solis & Michaela Marshall & Qing Yao & Rachel Garleb & Mengli Yang & Eric Pearlman & Scott G. Filler & Haoping Liu, 2024. "Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Tian-Yi Zhang & Yao-Qi Chen & Jing-Cong Tan & Jin-An Zhou & Wan-Ning Chen & Tong Jiang & Jin-Yin Zha & Xiang-Kang Zeng & Bo-Wen Li & Lu-Qi Wei & Yun Zou & Lu-Yao Zhang & Yue-Mei Hong & Xiu-Li Wang & R, 2024. "Global fungal-host interactome mapping identifies host targets of candidalysin," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Ilan Zaffran & Pratibha Gaur & Prince Ofori & Yoav Charpak-Amikam & Hadas Pahima & David Shasha & Nir Osherov & Bernhard Hube & Ronen Ben-Ami & Julian R. Naglik & Ofer Mandelboim & Joana Vitte & Franc, 2025. "Eosinophil CD48 interactions with Candida albicans Als6 is protective in vitro and in mouse systemic candidiasis," Nature Communications, Nature, vol. 16(1), pages 1-14, December.

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