Division of Fundamental Immunology, National African Swine Fever Para-reference Laboratory, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China; and.
College of Life Sciences, Yangtze University, Jingzhou 434025, China.
J Immunol. 2021 Dec 1;207(11):2754-2769. doi: 10.4049/jimmunol.2100320. Epub 2021 Nov 10.
African swine fever is a severe animal infectious disease caused by African swine fever virus (ASFV), and the morbidity and mortality associated with virulent ASFV isolates are as high as 100%. Previous studies showed that the ability of ASFV to antagonize IFN production is closely related to its pathogenicity. Here, we report that ASFV HLJ/18 infection induced low levels of type I IFN and inhibited cGMP-AMP-induced type I IFN production in porcine alveolar macrophages that were isolated from specific pathogen-free Landrace piglets. Subsequently, an unbiased screen was performed to screen the ASFV genes with inhibitory effects on the type I IFN production. ASFV pI215L, a viral E2 ubiquitin-conjugating enzyme, was identified as one of the strongest inhibitory effectors on the production of type I IFN. Knockdown of pI215L expression inhibited ASFV replication and enhanced IFN-β production. However, inhibition of type I IFN production by pI215L was independent of its E2 enzyme activity. Furthermore, we found that pI215L inhibited type I IFN production and K63-linked polyubiquitination of TANK-binding kinase 1 through pI215L-binding RING finger protein 138 (RNF138). ASFV pI215L enhanced the interaction between RNF138 and RNF128 and promoted RNF138 to degrade RNF128, which resulted in reduced K63-linked polyubiquitination of TANK-binding kinase 1 and type І IFN production. Taken together, our findings reveal a novel immune escape mechanism of ASFV, which provides a clue to the design and development of an immune-sensitive attenuated live vaccine.
非洲猪瘟是一种由非洲猪瘟病毒（ASFV）引起的严重动物传染病，高毒力 ASFV 分离株引起的发病率和死亡率高达 100%。先前的研究表明，ASFV 拮抗 IFN 产生的能力与其致病性密切相关。在这里，我们报告称，ASFV HLJ/18 感染诱导猪肺泡巨噬细胞中低水平的 I 型 IFN，并抑制来自无特定病原体长白仔猪的猪肺泡巨噬细胞中 cGMP-AMP 诱导的 I 型 IFN 产生。随后，进行了一项无偏筛选，以筛选具有抑制 I 型 IFN 产生作用的 ASFV 基因。ASFV pI215L，一种病毒 E2 泛素连接酶，被鉴定为对 I 型 IFN 产生具有最强抑制作用的效应物之一。pI215L 表达的敲低抑制了 ASFV 的复制并增强了 IFN-β 的产生。然而，pI215L 抑制 I 型 IFN 产生的作用不依赖于其 E2 酶活性。此外，我们发现 pI215L 通过 pI215L 结合 RING 指蛋白 138（RNF138）抑制 I 型 IFN 产生和 TANK 结合激酶 1 的 K63 连接多泛素化。ASFV pI215L 增强了 RNF138 和 RNF128 之间的相互作用，并促进 RNF138 降解 RNF128，从而导致 TANK 结合激酶 1 的 K63 连接多泛素化减少和 I 型 IFN 产生减少。总之，我们的研究结果揭示了 ASFV 的一种新的免疫逃避机制，为设计和开发免疫敏感减毒活疫苗提供了线索。
