National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China; Key Laboratory of Prevention & Control for African Swine Fever and Other Major Pig Diseases, Ministry of Agriculture and Rural Affairs, Wuhan, China; International Research Center for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, China.
Virus Res. 2023 Oct 2;335:199190. doi: 10.1016/j.virusres.2023.199190. Epub 2023 Aug 7.
African swine fever virus (ASFV) is an extensive and intricate double-stranded DNA virus with approximately 100% lethality in domestic swine. There is no effective vaccine to combat this virus, and this has led to substantial economic losses in the swine industry. ASFV encodes various proteins that impede interferon-based immune defenses in the host by employing diverse mechanisms. However, the roles of most of these proteins remain unknown. Therefore, understanding the immune evasion mechanisms employed by ASFV may facilitate the development of effective measures against the virus. In this study, we discovered a negative regulation of the type I interferon (IFN) response by the ASFV ribonuclease reductase large subunit pF778R. This novel type Ⅰ IFN response antagonist significantly inhibits IFN-α-induced interferon-stimulated response element promoter activation, precludes the upregulation of various interferon-stimulated genes, and prevents STAT1 nuclear translocation. Mechanistically, pF778R did not affect the protein levels of crucial molecules in the JAK/STAT signaling pathway or engage in direct interactions. However, pF778R expression impedes type I IFN responses mediated by the JAK/STAT signaling pathway. Further investigations revealed that pF778R did not interfere with STAT1 phosphorylation or dimerization, but it inhibited IFN signaling by weakening the nuclear accumulation of activated STAT1. The critical role of the ASFV protein pF778R in evading IFN-I-mediated innate immunity highlights a unique mode of ASFV evasion and provides insights into the pathogenic mechanism of the virus.
非洲猪瘟病毒（ASFV）是一种广泛而复杂的双链 DNA 病毒，对家猪的致死率约为 100%。目前尚无有效疫苗来对抗这种病毒，这导致了养猪业的巨大经济损失。ASFV 编码了多种蛋白，通过多种机制来阻止宿主基于干扰素的免疫防御。然而，这些蛋白的大多数功能仍然未知。因此，了解 ASFV 所采用的免疫逃避机制可能有助于开发针对该病毒的有效措施。在本研究中，我们发现 ASFV 的核糖核酸酶还原酶大亚基 pF778R 对 I 型干扰素（IFN）反应具有负调控作用。这种新型的Ⅰ型 IFN 反应拮抗剂显著抑制 IFN-α 诱导的干扰素刺激反应元件启动子激活，阻止各种干扰素刺激基因的上调，并阻止 STAT1 核转位。从机制上讲，pF778R 不影响 JAK/STAT 信号通路中关键分子的蛋白水平，也不与它们直接相互作用。然而，pF778R 表达会阻碍 JAK/STAT 信号通路介导的 I 型 IFN 反应。进一步的研究表明，pF778R 不干扰 STAT1 的磷酸化或二聚化，但它通过削弱激活的 STAT1 的核积累来抑制 IFN 信号。ASFV 蛋白 pF778R 在逃避 IFN-I 介导的先天免疫中的关键作用突出了 ASFV 逃避的一种独特模式，并为该病毒的致病机制提供了新的见解。
