EphA2 Is a Neutrophil Receptor for Candida albicans that Stimulates Antifungal Activity during Oropharyngeal Infection

During oropharyngeal candidiasis (OPC), Candida albicans proliferates and invades the superficial oral epithelium. Ephrin type-A receptor 2 (EphA2) functions as an oral epithelial cell beta-glucan receptor that triggers the production of proinflammatory mediators in response to fungal infection. Because EphA2 is also expressed by neutrophils, we investigated its role in neutrophil candidacidal activity during OPC. We found that EphA2 on stromal cells is required for the accumulation of phagocytes in the oral mucosa of mice with OPC. EphA2 on neutrophils is also central to host defense against OPC. The interaction of neutrophil EphA2 with serumopsonized C. albicans yeast activates the MEK-ERK signaling pathway, leading to NADPH subunit p47(P)(hOX) site-specific phospho-priming. This priming increases intracellular reactive oxygen species production and enhances fungal killing. Thus, in neutrophils, EphA2 serves as a receptor for beta-glucans that augments Fc gamma receptor-mediated antifungal activity and controls early fungal proliferation during OPC.