The globular C1q receptor is required for epidermal growth factor receptor signaling during Candida albicans infection

Abstract

During oropharyngeal candidiasis, Candida albicans activates the epidermal growth factor receptor (EGFR), which induces oral epithelial cells to both endocytose the fungus and synthesize proinflammatory mediators that orchestrate the host immune response. To elucidate the signaling pathways that are stimulated when C. albicans interacts with EGFR, we analyzed the proteins that associate with EGFR when C. albicans infects human oral epithelial cells. We identified 1214 proteins that were associated with EGFR in C. albicans-infected cells. We investigated the function of seven of these proteins that either showed increased association with EGFR in response to C. albicans or that mediated the interaction of other microbial pathogens with epithelial cells. Among these proteins, EGFR was found to associate with WW domain-binding protein 2, toll-interacting protein, interferon-induced transmembrane protein 3, and the globular C1q receptor (gC1qR) in viable epithelial cells. Each of these proteins was required for maximal endocytosis of C. albicans and they all regulated fungal-induced production of IL-1{beta} and/or IL-8, either positively or negatively. gC1qR functioned as a key coreceptor with EGFR. Interacting with the C. albicans Als3 invasin, gC1qR was required for the fungus to stimulate both EGFR and the ephrin type-A receptor 2. The combination of gC1qR and EGFR was necessary for maximal endocytosis of C. albicans and secretion of IL-1{beta}, IL-8, and GM-CSF. Thus, this work provides an atlas of proteins that associate with EGFR and identifies several that play a central role in the response of human oral epithelial cells to C. albicans infection. IMPORTANCEOral epithelial cells play a key role in the pathogenesis of oropharyngeal candidiasis. In addition to being target host cells for C. albicans adherence and invasion, they secrete proinflammatory cytokines and chemokines that recruit T cells and activated phagocytes to foci of infection. It is known that C. albicans activates EGFR on oral epithelial cells, which induces these cells to endocytose the organism and stimulates them to secrete proinflammatory mediators. To elucidate the EGFR signaling pathways that govern these responses, we analyzed the epithelial cell proteins that associate with EGFR in C. albicans-infected epithelial cells. We identified four proteins that physically associate with EGFR and that regulate different aspects of the epithelial response to C. albicans. One of these is gC1qR, which is required for C. albicans to activate EGFR, induce endocytosis, and stimulate the secretion of proinflammatory mediators, indicating that gC1qR functions as a key co-receptor with EGFR.