Oral epithelial cells discriminate between pathogenic and non-pathogenic stimuli, and only induce an inflammatory response when they are exposed to high levels of a potentially harmful microorganism. The pattern recognition receptors (PRRs) in epithelial cells that mediate this differential response are poorly understood. Here, we demonstrate that the ephrin type-A receptor 2 (EphA2) is an oral epithelial cell PRR that binds to exposed β-glucans on the surface of the fungal pathogen Candida albicans. Binding of C. albicans to EphA2 on oral epithelial cells activates signal transducer and activator of transcription 3 and mitogen-activated protein kinase signalling in an inoculum-dependent manner, and is required for induction of a proinflammatory and antifungal response. EphA2–/– mice have impaired inflammatory responses and reduced interleukin-17 signalling during oropharyngeal candidiasis, resulting in more severe disease. Our study reveals that EphA2 functions as a PRR for β-glucans that senses epithelial cell fungal burden and is required for the maximal mucosal inflammatory response to C. albicans.
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This work was supported in part by NIH grants R01DE022600 and R01AI124566 to S.G.F. and grant K99DE026856 to M.S. We are grateful to A.W. Orr and A.C. Finney for providing the EphA2–/– mice. We thank S.W. French and E. Vitocruz for histopathology; A.S. Ibrahim, M.R. Yeaman and J. Naglik for providing strains; and members of the Division of Infectious Diseases at Harbor-UCLA Medical Center for critical suggestions.
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