College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province, People's Republic of China.
Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Henan Agricultural University, Zhengzhou, Henan Province, People's Republic of China.
J Virol. 2021 Jul 26;95(16):e0076021. doi: 10.1128/JVI.00760-21.
Pseudorabies virus (PRV) is the causative pathogen of Aujeszky's disease in pigs. Although vaccination is currently applied to prevent the morbidity of PRV infection, new applications are urgently needed to control this infectious disease. Poly(ADP-ribose) polymerase 1 (PARP1) functions in DNA damage repair. We report here that pharmacological and genetic inhibition of PARP1 significantly influenced PRV replication. Moreover, we demonstrate that inhibition of PARP1 induced DNA damage response and antiviral innate immunity. Mechanistically, PARP1 inhibition-induced DNA damage response resulted in the release of double-stranded DNA (dsDNA) into the cytosol, where dsDNA interacted with cyclic GMP-AMP (cGAMP) synthase (cGAS). cGAS subsequently catalyzed cGAMP production to activate the STING/TBK1/IRF3 innate immune signaling pathway. Furthermore, challenge of mice with PARP1 inhibitor stimulated antiviral innate immunity and protected mice from PRV infection . Our results demonstrate that PARP1 inhibitors may be used as a new strategy to prevent Aujeszky's disease in pigs. Aujeszky's disease is a notifiable infectious disease of pigs and causes economic losses worldwide in the pig industry. The causative pathogen is PRV, which is a member of the subfamily of the family PRV has a wide range of hosts, such as ruminants, carnivores, and rodents. More seriously, recent reports suggest that PRV can cause human endophthalmitis and encephalitis, which indicates that PRV may be a potential zoonotic pathogen. Although vaccination is currently the major strategy used to control the disease, new applications are also urgently needed for the pig industry and public health. We report here that inhibition of PARP1 induces DNA damage-induced antiviral innate immunity through the cGAS-STING signaling pathway. Therefore, PARP1 is a therapeutic target for PRV infection as well as alphaherpesvirus infection.
伪狂犬病病毒（PRV）是猪 Aujeszky 病的病原体。尽管目前接种疫苗可用于预防 PRV 感染的发病率，但仍迫切需要新的应用来控制这种传染病。多聚（ADP-核糖）聚合酶 1（PARP1）在 DNA 损伤修复中发挥作用。我们在此报告，药理学和遗传学抑制 PARP1 显著影响 PRV 复制。此外，我们证明抑制 PARP1 诱导 DNA 损伤反应和抗病毒先天免疫。在机制上，PARP1 抑制诱导的 DNA 损伤反应导致双链 DNA（dsDNA）释放到细胞质中，dsDNA 与环鸟苷酸-AMP（cGAMP）合酶（cGAS）相互作用。cGAS 随后催化 cGAMP 产生以激活 STING/TBK1/IRF3 先天免疫信号通路。此外，用 PARP1 抑制剂挑战小鼠可刺激抗病毒先天免疫并保护小鼠免受 PRV 感染。我们的结果表明，PARP1 抑制剂可用作预防猪 Aujeszky 病的新策略。Aujeszky 病是一种猪的法定传染病，在全球养猪业中造成经济损失。病原体是 PRV，它是家族的亚科的成员。PRV 宿主范围广泛，如反刍动物、食肉动物和啮齿动物。更严重的是，最近的报告表明 PRV 可引起人类眼内炎和脑炎，这表明 PRV 可能是一种潜在的人畜共患病病原体。尽管目前疫苗接种是控制该病的主要策略，但养猪业和公共卫生也迫切需要新的应用。我们在此报告，抑制 PARP1 通过 cGAS-STING 信号通路诱导 DNA 损伤诱导的抗病毒先天免疫。因此，PARP1 是 PRV 感染以及α疱疹病毒感染的治疗靶标。
