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

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 (Stat3) and mitogen-activated protein kinase signaling in an inoculum-dependent manner, and is required for induction of a pro-inflammatory and antifungal response. EphA2−/− mice have impaired inflammatory responses and reduced IL-17 signaling during oropharyngeal candidiasis, resulting in more severe disease. Our study reveals that EphA2 functions as PRR for β-glucans that senses epithelial cell fungal burden and is required for the maximal mucosal inflammatory response to C. albicans.

New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

“…Interestingly, non-classical receptors including E-cadherin and EGFR/Her2 have been implicated in the epithelial recognition process (Phan et al, 2007;Sun et al, 2010;Zhu et al, 2012). More recently, EphA2 has been described as a β-glucan recognition receptor mediating immune responses by both oral epithelial cells (Swidergall et al, 2018) and neutrophils (Swidergall et al, 2019b), where it boosts Fcγ mediated antifungal responses such as reactive oxygen species (ROS) generation, and type 17 immunity. In addition, whilst the yeast form is the most immunogenic in the systemic environment, hyphae are the activating morphotype for mucosal surfaces (Moyes et al, 2010;Cheng et al, 2011).…”

“…This cytolysin has a dual effect, involved in both the induction of host cell damage and the development of immune responses by epithelial cells Naglik et al, 2019). Although EphA2 mediates C. albicans β-glucan recognition, secondary stimuli through different signaling circuits are still needed for the development of a proper immune response (Swidergall et al, 2018). In fact, candidalysin seems to be indispensable for driving pro-inflammatory outcomes in epithelial Richardson et al, 2017) and endothelial cells (Swidergall et al, 2019a).…”

Antifungal Innate Immunity: A Perspective from the Last 10 Years

“…Treatment with either a dual kinase inhibitor or an AhR inhibitor significantly reduced the severity of oropharyngeal candidiasis in mice [135, 136]. Furthermore, the receptor tyrosine kinase EphA2 was identified as a β-glucan receptor in oral epithelial cells involved in the control of fungal dissemination, as described above [78]. …”

“…Finally, recent work has identified the receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) as a β-glucan receptor in oral epithelial cells that is critical for mediating protective immunity during oral candidiasis. Binding of EphA2 to C. albicans activates STAT3 and MAPK signaling pathways required to induce proinflammatory cytokines, such as IL-17, to control fungal dissemination in a mouse model of oropharyngeal candidiasis [78]. …”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…A recent report showed that fungi also activate MEK and STAT3 through an ephrin type-A receptor 2 on oral epithelial cells. [121] Whether different types of fungi play different physiological activities and whether and how epithelial IKKα reduction regulates fungal infection remain to be revealed.…”