The vaccine strain against smallpox, vaccinia virus (VACV), is highly immunogenic yet causes relatively benign disease. These attributes are believed to be caused by gene loss in VACV. Using a targeted small interfering RNA (siRNA) screen, we identified a viral inhibitor found in cowpox virus (CPXV) and other orthopoxviruses that bound to the host SKP1-Cullin1-F-box (SCF) machinery and the essential necroptosis kinase receptor interacting protein kinase 3 (RIPK3). This “viral inducer of RIPK3 degradation” (vIRD) triggered ubiquitination and proteasome-mediated degradation of RIPK3 and inhibited necroptosis. In contrast to orthopoxviruses, the distantly related leporipoxvirus myxoma virus (MYXV), which infects RIPK3-deficient hosts, lacks a functional vIRD. Introduction of vIRD into VACV, which encodes a truncated and defective vIRD, enhanced viral replication in mice. Deletion of vIRD reduced CPXV-induced inflammation, viral replication, and mortality, which were reversed in RIPK3- and MLKL-deficient mice. Hence, vIRD-RIPK3 drives pathogen-host evolution and regulates virus-induced inflammation and pathogenesis.

天花疫苗株痘苗病毒 (VACV) 具有高度免疫原性，但会导致相对良性的疾病。这些属性被认为是由 VACV 中的基因丢失引起的。使用靶向小干扰 RNA (siRNA) 筛选，我们在牛痘病毒 (CPXV) 和其他正痘病毒中发现了一种病毒抑制剂，该病毒抑制剂与宿主 SKP1-Cullin1-F-box (SCF) 机制和必需的坏死性凋亡激酶受体相互作用蛋白结合激酶 3 (RIPK3)。这种“RIPK3 降解的病毒诱导剂”（vIRD）触发了泛素化和蛋白酶体介导的 RIPK3 降解并抑制了坏死性凋亡。与正痘病毒相比，感染 RIPK3 缺陷宿主的远缘兔痘病毒粘液瘤病毒 (MYXV) 缺乏功能性 vIRD。将 vIRD 引入 VACV，它编码截断和有缺陷的 vIRD，增强小鼠的病毒复制。vIRD 的缺失降低了 CPXV 诱导的炎症、病毒复制和死亡率，这在 RIPK3 和 MLKL 缺陷小鼠中得到了逆转。因此，vIRD-RIPK3 驱动病原体-宿主进化并调节病毒诱导的炎症和发病机制。