Show simple item record

dc.contributor.authorSolis, N.V.
dc.contributor.authorSwidergall, M.
dc.contributor.authorBruno, V.M.
dc.date.accessioned2019-07-15T16:16:59Z
dc.date.available2019-07-15T16:16:59Z
dc.date.issued2017
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85019154017&doi=10.1128%2fmBio.00025-17&partnerID=40&md5=f931fec8bb944079c5aee43af52fe4ec
dc.identifier.urihttp://hdl.handle.net/10713/10032
dc.description.abstractOropharyngeal candidiasis (OPC), caused predominantly by Candida albicans, is a prevalent infection in patients with advanced AIDS, defects in Th17 immunity, and head and neck cancer. A characteristic feature of OPC is fungal invasion of the oral epithelial cells. One mechanism by which C. albicans hyphae can invade oral epithelial cells is by expressing the Als3 and Ssa1 invasins that interact with the epidermal growth factor receptor (EGFR) on epithelial cells and stimulate endocytosis of the organism. However, the signaling pathways that function downstream of EGFR and mediate C. albicans endocytosis are poorly defined. Here, we report that C. albicans infection activates the aryl hydrocarbon receptor (Ah R), leading to activation of Src family kinases (SFKs), which in turn phosphorylate EGFR and induce endocytosis of the fungus. Furthermore, treatment of oral epithelial cells with interferon gamma inhibits fungal endocytosis by inducing the synthesis of kynurenines, which cause prolonged activation of Ah R and SFKs, thereby interfering with C. albicans-induced EGFR signaling. Treatment of both immunosuppressed and immunocompetent mice with an Ah R inhibitor decreases phosphorylation of SFKs and EGFR in the oral mucosa, reduces fungal invasion, and lessens the severity of OPC. Thus, our data indicate that Ah R plays a central role in governing the pathogenic interactions of C. albicans with oral epithelial cells during OPC and suggest that this receptor is a potential therapeutic target. IMPORTANCE OPC is caused predominantly by the fungus C. albicans, which can invade the oral epithelium by several mechanisms. One of these mechanisms is induced endocytosis, which is stimulated when fungal invasins bind to epithelial cell receptors such as EGFR. Receptor binding causes rearrangement of epithelial cell microfilaments, leading to the formation of pseudopods that engulf the fungus and pull it into the epithelial cell. We discovered Ah R acts via SFKs to phosphorylate EGFR and induce the endocytosis of C. albicans. Our finding that a small molecule inhibitor of Ah R ameliorates OPC in mice suggests that a strategy of targeting host cell signaling pathways that govern epithelial cell endocytosis of C. albicans holds promise as a new approach to preventing or treating OPC. Copyright 2017 Solis et al.en_US
dc.description.sponsorshipThis work was supported in part by NIH grants 1R01DE026600 (S.G.F. and V.M.B.), U19AI110820 (S.G.F. and V.M.B.), R01DE022550 (S.L.G.), and UL1TR001881 (S.G.F.).en_US
dc.description.urihttps://www.doi.org/10.1128/mBio.00025-17en_US
dc.language.isoen_USen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.relation.ispartofmBio
dc.subjectAryl hydrocarbon receptoren_US
dc.subjectCandida albicansen_US
dc.subjectEpithelial cellsen_US
dc.subjectHost cell invasionen_US
dc.subjectInterferon-gammaen_US
dc.titleThe aryl hydrocarbon receptor governs epithelial cell invasion during oropharyngeal candidiasisen_US
dc.typeArticleen_US
dc.identifier.doi10.1128/mBio.00025-17
dc.identifier.pmid28325761


This item appears in the following Collection(s)

Show simple item record