PUBLICATION
Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor
- Authors
- Ho, J., Yang, X., Nikou, S.A., Kichik, N., Donkin, A., Ponde, N.O., Richardson, J.P., Gratacap, R.L., Archambault, L.S., Zwirner, C.P., Murciano, C., Henley-Smith, R., Thavaraj, S., Tynan, C.J., Gaffen, S.L., Hube, B., Wheeler, R.T., Moyes, D.L., Naglik, J.R.
- ID
- ZDB-PUB-190528-11
- Date
- 2019
- Source
- Nature communications 10: 2297 (Journal)
- Registered Authors
- Wheeler, Robert
- Keywords
- none
- MeSH Terms
-
- Candida albicans/genetics
- Candida albicans/immunology*
- Candida albicans/metabolism
- Host-Pathogen Interactions/immunology*
- Zebrafish
- Mice, Inbred BALB C
- Phosphorylation
- Candidiasis/immunology
- Candidiasis/microbiology
- Humans
- Animals
- Matrix Metalloproteinases/immunology
- Matrix Metalloproteinases/metabolism
- Mice
- Disease Models, Animal
- Cell Line, Tumor
- Mucous Membrane/immunology
- Mucous Membrane/microbiology
- ErbB Receptors/genetics
- ErbB Receptors/immunology
- ErbB Receptors/metabolism
- Air Sacs/microbiology
- Epithelial Cells/immunology
- Epithelial Cells/metabolism
- Epithelial Cells/microbiology
- Female
- Pharyngitis/immunology
- Pharyngitis/microbiology
- MAP Kinase Signaling System/immunology
- Fungal Proteins/genetics
- Fungal Proteins/immunology*
- Fungal Proteins/metabolism
- PubMed
- 31127085 Full text @ Nat. Commun.
Citation
Ho, J., Yang, X., Nikou, S.A., Kichik, N., Donkin, A., Ponde, N.O., Richardson, J.P., Gratacap, R.L., Archambault, L.S., Zwirner, C.P., Murciano, C., Henley-Smith, R., Thavaraj, S., Tynan, C.J., Gaffen, S.L., Hube, B., Wheeler, R.T., Moyes, D.L., Naglik, J.R. (2019) Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor. Nature communications. 10:2297.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping