The Aryl Hydrocarbon Receptor Governs Epithelial Cell Invasion during Oropharyngeal Candidiasis.
Oropharyngeal candidiasis (OPC), caused predominantly byCandida 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 whichC. albicanshyphae 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 mediateC. albicansendocytosis are poorly defined. Here, we report thatC. albicansinfection activates the aryl hydrocarbon receptor (AhR), 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 AhR and SFKs, thereby interfering withC. albicans-induced EGFR signaling. Treatment of both immunosuppressed and immunocompetent mice with an AhR 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 AhR plays a central role in governing the pathogenic interactions ofC. albicanswith oral epithelial cells during OPC and suggest that this receptor is a potential therapeutic target.IMPORTANCEOPC is caused predominantly by the fungusC. 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 AhR acts via SFKs to phosphorylate EGFR and induce the endocytosis ofC. albicansOur finding that a small molecule inhibitor of AhR ameliorates OPC in mice suggests that a strategy of targeting host cell signaling pathways that govern epithelial cell endocytosis ofC. albicansholds promise as a new approach to preventing or treating OPC.
Division of Infectious Diseases, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
Norma V
NV
Solis
Division of Infectious Diseases, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
Marc
M
Swidergall
Institute for Genome Sciences and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Vincent M
VM
Bruno
Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Sarah L
SL
Gaffen
Division of Infectious Diseases, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA sfiller@ucla.edu.|Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Scott G
SG
Filler
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002180:Candidiasis, Oral / Q000382:microbiology* / Q000473:pathology*; D004195:Disease Models, Animal; D004705:Endocytosis; D004847:Epithelial Cells / Q000382:microbiology* / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D018336:Receptors, Aryl Hydrocarbon; D019061:src-Family Kinases; C484722:Ahr protein, mouse; C541485:EGFR protein, mouse
Candida albicans; aryl hydrocarbon receptor; epithelial cells; host cell invasion; interferon-gamma