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

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.

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