Herpes simplex virus type 1 disseminates from the cornea to the CNS in mice by thwarting type III interferon immune defenses.

Herpes simplex virus type 1 (HSV-1) can spread to the central nervous system (CNS) through the cornea to induce neurological diseases, but how HSV-1 overcomes corneal innate immunity to enter the CNS remains unclear. We report that HSV-1-infected cell protein 0 (ICP0) upregulates corneal suppressor of cytokine signaling 1 (SOCS1) and SOCS3 expression, which inhibits stimulator of interferon genes (STING)-interferon-λ (IFN-λ) signaling to promote virus escape to the CNS. Mechanistically, SOCS3 interacts with STING and induces K48-linked ubiquitination of STING at Lys275, which promotes STING degradation, ultimately suppressing corneal IFN-λ production. SOCS1 inhibits STAT1 activation against corneal IFN-λ antiviral responses. Administration of a STING agonist or IFN-λ preserves the corneal epithelial barrier and limits viral dissemination to the CNS. These findings elucidate an HSV-1 immune evasion mechanism in the cornea and highlight the potential of enhancing IFN-λ responses to prevent viral propagation to the CNS.