title: A STING-dependent innate-sensing pathway mediates resistance to corneal HSV-1 infection via upregulation of the antiviral effector tetherin.
abstract: Type 1 interferons (IFNs; IFNα/β) mediate immunological host resistance to numerous viral infections, including herpes simplex virus type 1 (HSV-1). The pathways responsible for IFNα/β signaling during the innate immune response to acute HSV-1 infection in the cornea are incompletely understood. Using a murine ocular infection model, we hypothesized that the stimulator of IFN genes (STING) mediates resistance to HSV-1 infection at the ocular surface and preserves the structural integrity of this mucosal site. Viral pathogenesis, tissue pathology, and host immune responses during ocular HSV-1 infection were characterized by plaque assay, esthesiometry, pachymetry, immunohistochemistry, flow cytometry, and small interfering RNA transfection in wild-type C57BL/6 (WT), STING-deficient (STING(-/-)), and IFNα/β receptor-deficient (CD118(-/-)) mice at days 3-5 postinfection. The presence of STING was critical for sustained control of HSV-1 replication in the corneal epithelium and resistance to viral neuroinvasion, but loss of STING had a negligible impact with respect to gross tissue pathology. Auxiliary STING-independent IFNα/β signaling pathways were responsible for maintenance of corneal integrity. Lymphatic vessels, mast cells, and sensory innervation were compromised in CD118(-/-) mice concurrent with increased tissue edema. STING-dependent signaling led to the upregulation of tetherin, a viral restriction factor we identify is important in containing the spread of HSV-1 in vivo.
authors.affiliation: Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Royer
authors.affiliation: Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Department of Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: D J J
authors.initials: DJ
authors.lastname: Carr
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003315:Cornea / Q000276:immunology* / Q000821:virology; D004195:Disease Models, Animal; D006561:Herpes Simplex / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014779:Virus Replication; D000074010:Bone Marrow Stromal Antigen 2; D000099197:STING Protein
chemical_list: D015703:Antigens, CD; D007370:Interferon Type I; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition; C513868:BST2 protein, mouse; D000074010:Bone Marrow Stromal Antigen 2; C530855:Sting1 protein, mouse; D000099197:STING Protein