Department of Immunology, Duke University School of Medicine, DUMC 3010, Durham, NC 27710, USA.
Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Immunity. 2021 Feb 9;54(2):247-258.e7. doi: 10.1016/j.immuni.2020.11.020. Epub 2021 Jan 13.
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，牛痘病毒（VACV），具有高度的免疫原性，但引起相对良性的疾病。这些属性被认为是由于 VACV 中的基因缺失引起的。使用靶向小干扰 RNA（siRNA）筛选，我们鉴定出一种存在于牛痘病毒（CPXV）和其他正痘病毒中的病毒抑制剂，该抑制剂与宿主 SKP1-Cullin1-F-box（SCF）机器和必需的坏死性凋亡受体相互作用蛋白激酶 3（RIPK3）结合。这种“病毒诱导的 RIPK3 降解物”（vIRD）触发 RIPK3 的泛素化和蛋白酶体介导的降解，并抑制坏死性凋亡。与正痘病毒相反，远亲兔痘病毒兔粘液瘤病毒（MYXV）感染 RIPK3 缺陷型宿主，缺乏功能正常的 vIRD。将 vIRD 引入编码截短和缺陷 vIRD 的 VACV 中，增强了在小鼠中的病毒复制。vIRD 的缺失减少了 CPXV 诱导的炎症、病毒复制和死亡率，而在 RIPK3 和 MLKL 缺陷型小鼠中则逆转了这些结果。因此，vIRD-RIPK3 驱动病原体-宿主的进化，并调节病毒诱导的炎症和发病机制。
