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Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor

Author

Listed:
  • Jemima Ho

    (King’s College London)

  • Xuexin Yang

    (King’s College London)

  • Spyridoula-Angeliki Nikou

    (King’s College London
    The Francis Crick Institute)

  • Nessim Kichik

    (King’s College London
    Imperial College London)

  • Andrew Donkin

    (King’s College London)

  • Nicole O. Ponde

    (King’s College London)

  • Jonathan P. Richardson

    (King’s College London)

  • Remi L. Gratacap

    (University of Maine
    University of Edinburgh)

  • Linda S. Archambault

    (University of Maine)

  • Christian P. Zwirner

    (University of Maine)

  • Celia Murciano

    (King’s College London
    Productos Citrosol)

  • Rhonda Henley-Smith

    (King’s College London)

  • Selvam Thavaraj

    (King’s College London)

  • Christopher J. Tynan

    (Rutherford Appleton Laboratory)

  • Sarah L. Gaffen

    (University of Pittsburgh)

  • Bernhard Hube

    (Hans Knöll Institute
    Friedrich Schiller University)

  • Robert T. Wheeler

    (University of Maine
    University of Maine)

  • David L. Moyes

    (King’s College London)

  • Julian R. Naglik

    (King’s College London)

Abstract

Candida albicans is a fungal pathobiont, able to cause epithelial cell damage and immune activation. These functions have been attributed to its secreted toxin, candidalysin, though the molecular mechanisms are poorly understood. Here, we identify epidermal growth factor receptor (EGFR) as a critical component of candidalysin-triggered immune responses. We find that both C. albicans and candidalysin activate human epithelial EGFR receptors and candidalysin-deficient fungal mutants poorly induce EGFR phosphorylation during murine oropharyngeal candidiasis. Furthermore, inhibition of EGFR impairs candidalysin-triggered MAPK signalling and release of neutrophil activating chemokines in vitro, and diminishes neutrophil recruitment, causing significant mortality in an EGFR-inhibited zebrafish swimbladder model of infection. Investigation into the mechanism of EGFR activation revealed the requirement of matrix metalloproteinases (MMPs), EGFR ligands and calcium. We thus identify a PAMP-independent mechanism of immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis.

Suggested Citation

  • Jemima Ho & Xuexin Yang & Spyridoula-Angeliki Nikou & Nessim Kichik & Andrew Donkin & Nicole O. Ponde & Jonathan P. Richardson & Remi L. Gratacap & Linda S. Archambault & Christian P. Zwirner & Celia , 2019. "Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09915-2
    DOI: 10.1038/s41467-019-09915-2
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    Cited by:

    1. 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.
    2. Xionghui Ding & Hiroto Kambara & Rongxia Guo & Apurva Kanneganti & Maikel Acosta-Zaldívar & Jiajia Li & Fei Liu & Ting Bei & Wanjun Qi & Xuemei Xie & Wenli Han & Ningning Liu & Cunling Zhang & Xiaoyu , 2021. "Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    3. Yuan Yang & Ruizeng Luo & Shengyu Chao & Jiangtao Xue & Dongjie Jiang & Yun Hao Feng & Xin Dong Guo & Dan Luo & Jiaping Zhang & Zhou Li & Zhong Lin Wang, 2022. "Improved pharmacodynamics of epidermal growth factor via microneedles-based self-powered transcutaneous electrical stimulation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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