Avian Immunosuppressive Diseases Division, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institutegrid.38587.31, Chinese Academy of Agricultural Sciences, Harbin, China.
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, China.
J Virol. 2022 Dec 21;96(24):e0157822. doi: 10.1128/jvi.01578-22. Epub 2022 Nov 30.
Cyclic GMP-AMP synthase (cGAS), a key DNA sensor, detects cytosolic viral DNA and activates the adaptor protein stimulator of interferon genes (STING) to initiate interferon (IFN) production and host innate antiviral responses. Duck enteritis virus (DEV) is a duck alphaherpesvirus that causes an acute and contagious disease with high mortality in waterfowl. In the present study, we found that DEV inhibits host innate immune responses during the late phase of viral infection. Furthermore, we screened DEV proteins for their ability to inhibit the cGAS-STING DNA-sensing pathway and identified multiple viral proteins, including UL41, US3, UL28, UL53, and UL24, which block IFN-β activation through this pathway. The DEV tegument protein UL41, which exhibited the strongest inhibitory effect, selectively downregulated the expression of interferon regulatory factor 7 (IRF7) by reducing its mRNA accumulation, thereby inhibiting the DNA-sensing pathway. Ectopic expression of UL41 markedly reduced viral DNA-triggered IFN-β production and promoted viral replication, whereas deficiency of UL41 in the context of DEV infection increased the IFN-β response to DEV and suppressed viral replication. In addition, ectopic expression of IRF7 inhibited the replication of the UL41-deficient virus, whereas IRF7 knockdown facilitated its replication. This study is the first report identifying multiple viral proteins encoded by a duck DNA virus, which inhibit the cGAS-STING DNA-sensing pathway. These findings expand our knowledge of DNA sensing in ducks and reveal a mechanism through which DEV antagonizes the host innate immune response. Duck enteritis virus (DEV) is a duck alphaherpesvirus that causes an acute and contagious disease with high mortality, resulting in substantial economic losses in the commercial waterfowl industry. The evasion of DNA-sensing pathway-mediated antiviral innate immunity is essential for the persistent infection and replication of many DNA viruses. However, the mechanisms used by DEV to modulate the DNA-sensing pathway remain poorly understood. In the present study, we found that DEV encodes multiple viral proteins to inhibit the cGAS-STING DNA-sensing pathway. The DEV tegument protein UL41 selectively diminished the accumulation of interferon regulatory factor 7 (IRF7) mRNA, thereby inhibiting the DNA-sensing pathway. Loss of UL41 potently enhanced the IFN-β response to DEV and impaired viral replication in ducks. These findings provide insights into the host-virus interaction during DEV infection and help develop new live attenuated vaccines against DEV.
环鸟苷酸-腺苷酸合成酶（cGAS）是一种关键的 DNA 传感器，可检测细胞质中的病毒 DNA，并激活干扰素基因刺激物（STING）衔接蛋白，从而启动干扰素（IFN）的产生和宿主固有抗病毒反应。鸭肠炎病毒（DEV）是一种鸭α疱疹病毒，可引起水禽急性和传染性疾病，死亡率高。在本研究中，我们发现 DEV 在病毒感染的晚期抑制宿主固有免疫反应。此外，我们筛选了 DEV 蛋白抑制 cGAS-STING DNA 传感途径的能力，并鉴定了多种病毒蛋白，包括 UL41、US3、UL28、UL53 和 UL24，它们通过该途径阻断 IFN-β的激活。具有最强抑制作用的 DEV 包膜蛋白 UL41 通过减少其 mRNA 积累选择性地下调干扰素调节因子 7（IRF7）的表达，从而抑制 DNA 传感途径。UL41 的异位表达显著降低了病毒 DNA 触发的 IFN-β产生并促进了病毒复制，而在 DEV 感染的情况下缺乏 UL41 则增加了对 DEV 的 IFN-β反应并抑制了病毒复制。此外，IRF7 的异位表达抑制了 UL41 缺陷病毒的复制，而 IRF7 的敲低则促进了其复制。这项研究首次鉴定了一种鸭 DNA 病毒编码的多种病毒蛋白，这些蛋白抑制了 cGAS-STING DNA 传感途径。这些发现扩展了我们对鸭中 DNA 传感的认识，并揭示了 DEV 拮抗宿主固有免疫反应的机制。鸭肠炎病毒（DEV）是一种鸭α疱疹病毒，可引起急性和传染性疾病，死亡率高，给商业水禽产业造成巨大经济损失。逃避 DNA 传感途径介导的抗病毒固有免疫对于许多 DNA 病毒的持续感染和复制至关重要。然而，DEV 用来调节 DNA 传感途径的机制仍知之甚少。在本研究中，我们发现 DEV 编码多种病毒蛋白来抑制 cGAS-STING DNA 传感途径。DEV 包膜蛋白 UL41 选择性地减少干扰素调节因子 7（IRF7）mRNA 的积累，从而抑制 DNA 传感途径。UL41 的缺失强烈增强了 DEV 对 IFN-β的反应并损害了鸭中的病毒复制。这些发现为 DEV 感染期间的宿主-病毒相互作用提供了新的见解，并有助于开发针对 DEV 的新型活减毒疫苗。
