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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • 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

摘要

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.