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EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans

Nature Microbiology volume 3, pages 53–61 (2018)Cite this article

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An Author Correction to this article was published on 12 June 2018

A Publisher Correction to this article was published on 13 February 2018

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Abstract

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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Fig. 1: EphA2 is bound and activated by β-glucans.
Fig. 2: EphA2 and dectin-1 regulate distinct host response pathways in oral epithelial cells.
Fig. 3: EphA2 signalling regulates the inflammatory response.
Fig. 4: Higher fungal inoculum induces stronger host response.
Fig. 5: EphA2 signalling maintains mucosal immunity during OPC.
Fig. 6: EphA2 on oral epithelial cells binds β-glucan and primes the cells for an inflammatory response.

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Change history

  • 12 June 2018

    In the version of this Article originally published, the authors described the ANT compound used in their study as 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-hydroxybenzoic acid (ANT). The authors now wish to clarify that the ANT compound used was actually a 2,5-dimethylpyrrolyl benzoic acid derivative1 that has been shown to inhibit not only the enzymatic activity of EphA2, but also several unrelated enzymes2. The description of the compound in the Article has now been changed to 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-hydroxybenzoic acid derivative (ANT) to reflect this.

  • 13 February 2018

    In the version of this Article originally published, technical problems led to errors in Figs. 2d and 5b. In the western blot panel in Fig. 2d, actin bands were misaligned at the bottom of the image and did not line up with the other bands in the panel; the corrected figure is shown below. In Fig. 5b, the upper right panel had an incorrect title of ‘CXCL3/KC’; it should have instead been ‘CXCL1/KC’. These errors have now been corrected in all versions of the Article.

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Acknowledgements

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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Authors and Affiliations

  1. Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA

    Marc Swidergall, Norma V. Solis & Scott G. Filler

  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, Bethesda, MD, USA

    Michail S. Lionakis

  3. David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Scott G. Filler

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  1. Marc Swidergall
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Contributions

M.S., N.V.S., M.S.L. and S.G.F. designed the experiments. M.S. and N.V.S. performed the experiments. M.S., N.V.S., M.S.L. and S.G.F. analysed the data. M.S. and S.G.F. wrote the paper.

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Correspondence to Scott G. Filler.

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Competing interests

S.G.F. is a co-founder of and shareholder in NovaDigm Therapeutics, Inc., a company that is developing a vaccine against mucosal and invasive Candida infections.

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Supplementary Tables 1–3, Supplementary Figures 1–34.

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Swidergall, M., Solis, N.V., Lionakis, M.S. et al. EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans. Nat Microbiol 3, 53–61 (2018). https://doi.org/10.1038/s41564-017-0059-5

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