The Candida albicans toxin candidalysin mediates distinct epithelial inflammatory responses through p38 and EGFR-ERK pathways.

Abstract

The fungal pathogen Candida albicans secretes the peptide toxin candidalysin, which damages epithelial cells and drives an innate inflammatory response mediated by the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) pathways and the transcription factor c-Fos. In cultured oral epithelial cells (OECs), candidalysin activated the p38 MAPK signaling pathway, which resulted in heat shock protein 27 (Hsp27) activation, IL-6 release, and EGFR phosphorylation without influencing the induction of c-Fos. p38 activation was not triggered by EGFR but by two non-redundant pathways involving MAPK kinases (MKKs) and the kinase Src, which differentially controlled p38 signaling outputs. Whereas MKKs mainly promoted p38-dependent release of IL-6, Src promoted p38-mediated phosphorylation of EGFR in a ligand-independent fashion. In parallel, candidalysin also activated the EGFR-ERK pathway in a manner that depended on EGFR ligands, resulting in c-Fos activation and release of the neutrophil-activating chemokines G-CSF and GM-CSF. In mice, p38 was important for the early clearance events of oral C. albicans infection, but c-Fos was not. These findings delineate how candidalysin activates the p38 and ERK MAPK pathways that differentially contribute to immune activation during C. albicans infection.