A STING-dependent innate-sensing pathway mediates resistance to corneal HSV-1 infection via upregulation of the antiviral effector tetherin

Type 1 interferons (IFNα/β) mediate immunologic host resistance to numerous viral infections including herpes simplex virus type 1 (HSV-1). The pathways responsible for maintenance of 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 host resistance to HSV-1 infection in the external ocular surface and preserves the structural integrity of this immune privileged mucosal site. Viral pathogenesis, tissue pathology, and host immune responses during ocular HSV-1 infection were evaluated and characterized by plaque assay, esthesiometry, pachymetry, immunohistochemistry, flow cytometry, and siRNA transfection in wildtype C57BL/6 (WT), STING-deficient (STING-/-), and IFNα/β receptor-deficient (CD118-/-) mice at days 3-5 post infection (pi). The presence of STING was critical for sustained control of HSV-1 replication in the corneal epithelium and 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 the 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 to be important in containing the spread of HSV-1 in vivo.