{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:30:48Z","timestamp":1790353848679,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009221","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000}}],"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T00:00:00Z","timestamp":1611100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R00DE026856"],"award-info":[{"award-number":["R00DE026856"]}]},{"name":"NIH","award":["R21AI144878"],"award-info":[{"award-number":["R21AI144878"]}]},{"name":"NIH","award":["R01DE022600"],"award-info":[{"award-number":["R01DE022600"]}]},{"name":"NIH","award":["R01AI124566"],"award-info":[{"award-number":["R01AI124566"]}]},{"name":"LA BioMed Summer Fellowship Program."}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>During oropharyngeal candidiasis (OPC),<jats:italic>Candida albicans<\/jats:italic>invades and damages oral epithelial cells, which respond by producing proinflammatory mediators that recruit phagocytes to foci of infection. The ephrin type-A receptor 2 (EphA2) detects \u03b2-glucan and plays a central role in stimulating epithelial cells to release proinflammatory mediators during OPC. The epidermal growth factor receptor (EGFR) also interacts with<jats:italic>C<\/jats:italic>.<jats:italic>albicans<\/jats:italic>and is known to be activated by the Als3 adhesin\/invasin and the candidalysin pore-forming toxin. Here, we investigated the interactions among EphA2, EGFR, Als3 and candidalysin during OPC. We found that EGFR and EphA2 constitutively associate with each other as part of a heteromeric physical complex and are mutually dependent for<jats:italic>C<\/jats:italic>.<jats:italic>albicans-<\/jats:italic>induced activation. Als3-mediated endocytosis of a<jats:italic>C<\/jats:italic>.<jats:italic>albicans<\/jats:italic>hypha leads to the formation of an endocytic vacuole where candidalysin accumulates at high concentration. Thus, Als3 potentiates targeting of candidalysin, and both Als3 and candidalysin are required for<jats:italic>C<\/jats:italic>.<jats:italic>albicans<\/jats:italic>to cause maximal damage to oral epithelial cells, sustain activation of EphA2 and EGFR, and stimulate pro-inflammatory cytokine and chemokine secretion. In the mouse model of OPC,<jats:italic>C<\/jats:italic>.<jats:italic>albicans-<\/jats:italic>induced production of CXCL1\/KC and CCL20 is dependent on the presence of candidalysin and EGFR, but independent of Als3. The production of IL-1\u03b1 and IL-17A also requires candidalysin but is independent of Als3 and EGFR. The production of TNF\u03b1 requires Als1, Als3, and candidalysin. Collectively, these results delineate the complex interplay among host cell receptors EphA2 and EGFR and<jats:italic>C<\/jats:italic>.<jats:italic>albicans<\/jats:italic>virulence factors Als1, Als3 and candidalysin during the induction of OPC and the resulting oral inflammatory response.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009221","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T19:40:53Z","timestamp":1611171653000},"page":"e1009221","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":88,"title":["Activation of EphA2-EGFR signaling in oral epithelial cells by Candida albicans virulence factors"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5261-6267","authenticated-orcid":true,"given":"Marc","family":"Swidergall","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma 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