Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor

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 Murciano, Rhonda Henley-Smith, Selvam Thavaraj, Christopher J. Tynan, Sarah L. Gaffen, Bernhard Hube, Robert T. Wheeler, David L. Moyes and Julian R. Naglik ()
Additional contact information
Jemima Ho: King’s College London
Xuexin Yang: King’s College London
Spyridoula-Angeliki Nikou: King’s College London
Nessim Kichik: King’s 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
Linda S. Archambault: University of Maine
Christian P. Zwirner: University of Maine
Celia Murciano: King’s College London
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
Robert T. Wheeler: University of Maine
David L. Moyes: King’s College London
Julian R. Naglik: King’s College London

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09915-2

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