Activation of the epidermal growth factor receptor initiates innate immune responses during oropharyngeal candidiasis

Abstract

During oropharyngeal candidiasis (OPC), Candida albicans invades and damages oral epithelial cells, which respond by producing proinflammatory mediators that recruit phagocytes to foci of infection. The ephrin type-A receptor 2 (EphA2) detects {beta}-glucan and plays a central role in stimulating epithelial cells to release proinflammatory mediators during OPC. The epidermal growth factor receptor (EGFR) also interacts with C. albicans and is known to be activated by the Als3 adhesin/invasin and the Ece1/Candidalysin pore-forming toxin. Here, we investigated the interactions among EphA2, EGFR, Als3 and Ece1/Candidalysin during OPC. We found that Als3 and Ece1/Candidalysin function in the same pathway to damage epithelial cells in vitro. They also work together to cause OPC in mice. EGFR and EphA2 constitutively associate with each other as part of a physical complex and are mutually dependent for C. albicans-induced activation. In vitro, either Als3 or Ece1/Candidalysin is required for C. albicans to activate EGFR, sustain EphA2 activation, and stimulate epithelial cells to secrete CXCL8/IL-8 and CCL20. In the mouse model of OPC, Ece1/Candidalysin alone activates EGFR and induces CXCL1/KC and CCL20 production. Ece1/Candidalysin is also necessary for the production of IL-1 and IL-17A independently of Als3 and EGFR. These results delineate the complex interplay between host cell receptors and C. albicans virulence factors during the induction of OPC and the resulting oral inflammatory response. Author summaryOropharyngeal candidiasis occurs when the fungus Candida albicans proliferates in the mouth. The disease is characterized by fungal invasion of the superficial epithelium and a localized inflammatory response. Two C. albicans virulence factors contribute to the pathogenesis of OPC, Als3 which enables the organisms to adhere to and invade host cells and Ece1/Candidalysin which is pore-forming toxin that damages host cells. Two epithelial cell receptors, ephrin type-A receptor 2 (EphA2) and the epidermal growth factor receptor (EGFR) are activated by C. albicans. Here, we show that EphA2 and EGFR form part of complex and that each receptor is required to activate the other. Als3 and Ece1/Candidalysin function in the same pathway to damage epithelial cells. In isolated epithelial cells, both of these virulence factors activate EphA2 and EGFR, and stimulate the production of inflammatory mediators. In the mouse model of OPC, Ece1/Candidalysin elicits of a subset of the oral inflammatory response. Of the cytokines and chemokines induced by this toxin, some require the activation of EGFR while others are induced independently of EGFR. This work provides a deeper understanding of the interactions among C. albicans virulence factors and host cell receptors during OPC.