EphA2 is a Neutrophil Receptor for Candida Albicans that Stimulates Antifungal Activity During Oropharyngeal Infection

Abstract

During oropharyngeal candidiasis (OPC), Candida albicans proliferates and invades the superficial oral epithelium. The ephrin type-A receptor 2 (EphA2) functions as an oral epithelial cell β-glucan receptor that triggers the production of proinflammatory mediators in response to fungal infection. Because EphA2 is also expressed by neutrophils, we investigated the role of EphA2 in neutrophil candidacidal activity during OPC. We found that when OPC was induced in EphA2–/– mice, there was delayed accumulation of phagocytes in the oral tissues and more severe disease relative to wild-type mice. Depletion of neutrophils in EphA2–/– mice did not further increase oral fungal burden, nor did adoptive transfer of EphA2–/– neutrophils into CD18−/− mice decrease oral fungal burden, indicating that EphA2 on neutrophils plays a central role in the host defense against OPC. Mice lacking the Fcγ receptor I were also highly susceptible to OPC. In vitro studies showed that EphA2 signaling augments neutrophil Fcγ receptor-mediated antifungal activity. The interaction of serum-opsonized C. albicans yeast with neutrophil EphA2 activated the MEK-ERK signaling pathway, leading to NADPH subunit p47phox site specific phospho-priming. EphA2-induced priming of neutrophil p47phox increased intracellular ROS production and enhanced killing of opsonized C. albicans yeast. Thus, in neutrophils, EphA2 serves as a receptor for β-glucans that enhances Fcγ receptor-mediated antifungal activity and is crucial to control early fungal proliferation during OPC.