Wei Liu, Haifeng Cui, Li Wang, Xiangyu Ge, Xingfei Zhu, Xingmiao Liang, Ziqing Chen, Yuwen Gan, Le Shi, Xuebin Hu, Xiaohu Ding, Zhengjie Xu, Xiaoling Liang, Lili Gong
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.