Candida albicansstimulates the formation of a multi-receptor complex that mediates epithelial cell invasion during oropharyngeal infection

Abstract

SummaryFungal invasion of the oral epithelium is central to the pathogenesis of oropharyngeal candidiasis (OPC).Candida albicansinvades the oral epithelium by receptor-induced endocytosis but this process is incompletely understood. We found thatC. albicansinfection of oral epithelial cells induces c-Met to form a multi-protein complex with E-cadherin and the epidermal growth factor receptor (EGFR). E-cadherin is necessary forC. albicansto activate both c-Met and EGFR and to induce the endocytosis ofC. albicans. Proteomics analysis revealed that c-Met interacts withC. albicansHyr1, Als3 and Ssa1. Both Hyr1 and Als3 were required forC. albicansstimulation of c-Met and EGFR in oral epithelial cells in vitro and for full virulence during OPC in mice. Treating mice with small molecule inhibitors of c-Met and EGFR ameliorated OPC, demonstrating the potential therapeutic efficacy of blocking these host receptors forC. albicans.Graphical abstractHighlightsc-Met is an oral epithelial cell receptor forCandida albicansC. albicansinfection causes c-Met and the epidermal growth factor receptor (EGFR) to form a complex with E-cadherin, which is required for c-Met and EGFR functionC. albicansHyr1 and Als3 interact with c-Met and EGFR, inducing oral epithelial cell endocytosis and virulence during oropharyngeal candidiasisDual blockade of c-Met and EGFR ameliorates oropharyngeal candidiasis