Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor

• Published in: Nature communications Vol. 10; no. 1; pp. 2297 - 12
• Main Authors: Ho, Jemima, Yang, Xuexin, Nikou, Spyridoula-Angeliki, Kichik, Nessim, Donkin, Andrew, Ponde, Nicole O., Richardson, Jonathan P., Gratacap, Remi L., Archambault, Linda S., Zwirner, Christian P., Murciano, Celia, Henley-Smith, Rhonda, Thavaraj, Selvam, Tynan, Christopher J., Gaffen, Sarah L., Hube, Bernhard, Wheeler, Robert T., Moyes, David L., Naglik, Julian R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.05.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/19; 49/40; 631/250/255/1672; 631/250/262; 631/326/193/2544; 631/80/86/2368; 64/116; 64/60; 82/103; 82/51; 82/80; 96; 96/1; 96/106; 96/109; 96/21; 96/31; Air Sacs - microbiology; Animals; Calcium; Candida albicans; Candida albicans - genetics; Candida albicans - immunology; Candida albicans - metabolism; Candidiasis; Candidiasis - immunology; Candidiasis - microbiology; Cell activation; Cell Line, Tumor; Chemokines; Critical components; Disease Models, Animal; Epidermal growth factor; Epidermal growth factor receptors; Epithelial cells; Epithelial Cells - immunology; Epithelial Cells - metabolism; Epithelial Cells - microbiology; ErbB Receptors - genetics; ErbB Receptors - immunology; ErbB Receptors - metabolism; Female; Fungal Proteins - genetics; Fungal Proteins - immunology; Fungal Proteins - metabolism; Fungi; Growth factors; Host-Pathogen Interactions - immunology; Humanities and Social Sciences; Humans; Immune response; MAP kinase; MAP Kinase Signaling System - immunology; Matrix metalloproteinase; Matrix metalloproteinases; Matrix Metalloproteinases - immunology; Matrix Metalloproteinases - metabolism; Mice; Mice, Inbred BALB C; Molecular modelling; Mucosa; Mucous membrane; Mucous Membrane - immunology; Mucous Membrane - microbiology; multidisciplinary; Neutrophils; Pharyngitis - immunology; Pharyngitis - microbiology; Phosphorylation; Receptors; Science; Science (multidisciplinary); Signaling; Swim bladder; Toxins; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09915-2

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. Candida albicans is an opportunistic fungus primarily affecting immunocompromised patients. Here, the authors identify a novel mechanism of host immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis.