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; Julian R Naglik

doi:10.1038/s41467-019-09915-2

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, Julian R Naglik

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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.

Original language	English
Article number	2297
Journal	Nature Communications
Volume	10
Issue number	1
Early online date	24 May 2019
DOIs	https://doi.org/10.1038/s41467-019-09915-2
Publication status	Published - 1 Dec 2019

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Candidalysin activates innate epithelial_HO_Accepted9April2019Publishedonline24May2019_GOLD VoR (CC BY)Final published version, 2.08 MBLicence: CC BY

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Ho, J., Yang, X., Nikou, S. A., Kichik, N., Donkin, A., Ponde, N. O., Richardson, J. P., L. Gratacap, R., S. Archambault, L., P. Zwirner, C., Murciano, C., Henley-Smith, R., Thavaraj, S., J. Tynan, C., L. Gaffen, S., Hube, B., T. Wheeler, R., Moyes, D. L., & Naglik, J. R. (2019). Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor. Nature Communications, 10(1), Article 2297. https://doi.org/10.1038/s41467-019-09915-2

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title = "Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor",

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.",

author = "Jemima Ho and Xuexin Yang and Nikou, {Spyridoula Angeliki} and Nessim Kichik and Andrew Donkin and Ponde, {Nicole O.} and Richardson, {Jonathan P} and {L. Gratacap}, Remi and {S. Archambault}, Linda and {P. Zwirner}, Christian and Celia Murciano and Rhonda Henley-Smith and Selvam Thavaraj and {J. Tynan}, Christopher and {L. Gaffen}, Sarah and Bernhard Hube and {T. Wheeler}, Robert and Moyes, {David L} and Naglik, {Julian R}",

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Ho, J, Yang, X, Nikou, SA , Kichik, N, Donkin, A, Ponde, NO , Richardson, JP, L. Gratacap, R, S. Archambault, L, P. Zwirner, C, Murciano, C, Henley-Smith, R, Thavaraj, S, J. Tynan, C, L. Gaffen, S, Hube, B, T. Wheeler, R, Moyes, DL & Naglik, JR 2019, 'Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor', Nature Communications, vol. 10, no. 1, 2297. https://doi.org/10.1038/s41467-019-09915-2

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T1 - Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor

AU - Ho, Jemima

AU - Yang, Xuexin

AU - Nikou, Spyridoula Angeliki

AU - Kichik, Nessim

AU - Donkin, Andrew

AU - Ponde, Nicole O.

AU - Richardson, Jonathan P

AU - L. Gratacap, Remi

AU - S. Archambault, Linda

AU - P. Zwirner, Christian

AU - Murciano, Celia

AU - Henley-Smith, Rhonda

AU - Thavaraj, Selvam

AU - J. Tynan, Christopher

AU - L. Gaffen, Sarah

AU - Hube, Bernhard

AU - T. Wheeler, Robert

AU - Moyes, David L

AU - Naglik, Julian R

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2297

ER -

Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor

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