EphA2 Is a Neutrophil Receptor for Candida albicans that Stimulates Antifungal Activity during Oropharyngeal Infection
Marc Swidergall,
Norma V. Solis,
Zeping Wang,
Quynh T. Phan,
Michaela E. Marshall,
Michail S. Lionakis,
Eric Pearlman,
Scott G. Filler
Affiliations
Marc Swidergall
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA 90502, USA; Institute for Infection and Immunity, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA; Corresponding author
Norma V. Solis
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA 90502, USA; Institute for Infection and Immunity, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
Zeping Wang
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA 90502, USA
Quynh T. Phan
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA 90502, USA; Institute for Infection and Immunity, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
Michaela E. Marshall
Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA
Michail S. Lionakis
Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892, USA
Eric Pearlman
Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA
Scott G. Filler
Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA 90502, USA; Institute for Infection and Immunity, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA; Corresponding author
Summary: 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 β-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 serum-opsonized C. albicans yeast activates the MEK-ERK signaling pathway, leading to NADPH subunit p47phox 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 β-glucans that augments Fcγ receptor-mediated antifungal activity and controls early fungal proliferation during OPC. : In oral epithelial cells, EphA2 functions as a β-glucan receptor that triggers the production of proinflammatory mediators in response to oropharyngeal candidiasis. Here, Swidergall et al. show that, in neutrophils, EphA2 recognition of β-glucans augments Fcγ receptor-mediated antifungal activity and prevents fungal proliferation during the initiation of oropharyngeal infection. Keywords: Candida albicans, EphA2, neutrophil, oropharyngeal candidiasis, pattern recognition receptor, innate immunity
