TY - JOUR T1 - Activation of the epidermal growth factor receptor initiates innate immune responses during oropharyngeal candidiasis JF - bioRxiv DO - 10.1101/491076 SP - 491076 AU - Marc Swidergall AU - Norma V. Solis AU - Quynh T. Phan AU - Michael D. Lazarus AU - Zeping Wang AU - Scott G. Filler Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/12/09/491076.abstract N2 - The induction of antifungal proinflammatory signaling during oropharyngeal candidiasis (OPC) is crucial to limit Candida albicans proliferation and induce fungal clearance. Previously, we determined that the ephrin type-A receptor 2 (EphA2) functions as a β-glucan receptor that senses oral epithelial cell fungal burden. EphA2 plays a central role in stimulating the epithelial cell release of proinflammatory mediators that mediate resistance to OPC. Another receptor for C. albicans is the epidermal growth factor receptor (EGFR), which interacts with candidal invasins such as Als3 interact and induces epithelial cells to endocytose the fungus. Here, we investigated the interactions between EGFR and EphA2. We found that EGFR and EphA2 constitutively associated with each other as part of a physical complex. Activation of EGFR by C. albicans Als3 was required for sustained EphA2 phosphorylation and for induction of CXCL8/IL-8 and CCL20 secretion by epithelial cells. Treatment of uninfected epithelial cells with IL-17A and TNFα also induced EGFR phosphorylation, which was necessary for epithelial cells to respond to these cytokines. In mice with OPC, pharmacological inhibition of EGFR during caused a modest reduction in oral fungal burden, markedly impaired production of proinflammatory cytokines and significantly decreased accumulation of neutrophils and inflammatory monocytes. Thus, while C. albicans activation of EGFR mediates fungal invasion of the epithelium, it also sustains EphA2 signaling, inducing the epithelial cell proinflammatory response to the fungus.Importance Host cell receptors for fungi have typically been evaluated from one of two different perspectives, their role in inducing the invasion of the organism or their role in stimulating the host inflammatory response. We had found previously that EGFR mediates the endocytosis of C. albicans by oral epithelial cells, and that epithelial cell EphA2 mediates the production of chemokines and proinflammatory cytokines in response to C. albicans. Here, we demonstrate that EGFR and EphA2 interact with each other, both physically and functionally. EGFR is required for sustained EphA2 activation and for epithelial cells to secrete proinflammatory mediators in response to both C. albicans and IL-17A. Therefore, while activation of EGFR by C. albicans enhances pathogenicity by inducing the endocytosis of the fungus, it also augments the host defense against OPC by stimulating the host inflammatory response. ER -