STING activates ZBP1-mediated PANoptosis to defend against HSV-1 retinal infection.

Herpes simplex virus type 1 (HSV-1) is the most common cause of infectious blindness and is a major cause of acute retinal necrosis (ARN), a severe condition marked by rapid necrosis of the retina. Effective treatments for HSV-1 retinal infection are limited to general antiviral drugs, which do not specifically target the underlying pathophysiology. Here, we investigate the role of stimulator of interferon genes (STING), a key player in innate immunity, in HSV-1 retinal infections. STING knockout (KO) mice are highly susceptible to HSV-1 retinal infection, evidenced by impaired antiviral immune responses, increased ocular virus load and severe retinal necrosis. Mechanistically, STING is required for Z-DNA binding protein 1 (ZBP1)-mediated PANoptosis, an inflammatory programmed cell death pathway, in microglia and macrophages. STING forms a complex with ZBP1 and Z-form nuclei acid during HSV-1 infection. Further, activation of STING induced Z-form nuclei acid and subsequent activation of ZBP1. ZBP1 KO mice exhibited a similar defective antiviral phenotype as STING KO mice, whereas treatment with ZBP1 agonist Curaxin CBL0137 rescued the impaired antiviral response in STING-deficient microglia and macrophages and mitigates retinal necrosis in both WT and STING KO mice following HSV-1 infection. Together, our study revealed a STING-ZBP1-PANoptosis signal axis against HSV-1 infection in retina, which should provide new insights for the treatment of retinal virus infection such as ARN.