Division of Fundamental Immunology, National African Swine Fever Para-reference Laboratory, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
Heilongjiang Provincial Key Laboratory of Veterinary Immunology, Harbin, China.
J Virol. 2024 Mar 19;98(3):e0183423. doi: 10.1128/jvi.01834-23. Epub 2024 Feb 14.
African swine fever (ASF) is an acute, hemorrhagic, and severe infectious disease caused by ASF virus (ASFV) infection. At present, there are still no safe and effective drugs and vaccines to prevent ASF. Mining the important proteins encoded by ASFV that affect the virulence and replication of ASFV is the key to developing effective vaccines and drugs. In this study, ASFV pH240R, a capsid protein of ASFV, was found to inhibit the type I interferon (IFN) signaling pathway. Mechanistically, pH240R interacted with IFNAR1 and IFNAR2 to disrupt the interaction of IFNAR1-TYK2 and IFNAR2-JAK1. Additionally, pH240R inhibited the phosphorylation of IFNAR1, TYK2, and JAK1 induced by IFN-α, resulting in the suppression of the nuclear import of STAT1 and STAT2 and the expression of IFN-stimulated genes (ISGs). Consistent with these results, H240R-deficient ASFV (ASFV-∆H240R) infection induced more ISGs in porcine alveolar macrophages compared with its parental ASFV HLJ/18. We also found that pH240R enhanced viral replication via inhibition of ISGs expression. Taken together, our results clarify that pH240R enhances ASFV replication by inhibiting the JAK-STAT signaling pathway, which highlights the possibility of pH240R as a potential drug target.IMPORTANCEThe innate immune response is the host's first line of defense against pathogen infection, which has been reported to affect the replication and virulence of African swine fever virus (ASFV) isolates. Identification of ASFV-encoded proteins that affect the virulence and replication of ASFV is the key step in developing more effective vaccines and drugs. In this study, we found that pH240R interacted with IFNAR1 and IFNAR2 by disrupting the interaction of IFNAR1-TYK2 and IFNAR2-JAK1, resulting in the suppression of the expression of interferon (IFN)-stimulated genes (ISGs). Consistent with these results, H240R-deficient ASFV (ASFV-∆H240R) infection induces more ISGs' expression compared with its parental ASFV HLJ/18. We also found that pH240R enhanced viral replication via inhibition of ISGs' expression. Taken together, our findings showed that pH240R enhances ASFV replication by inhibiting the IFN-JAK-STAT axis, which highlights the possibility of pH240R as a potential drug target.
非洲猪瘟（ASF）是由非洲猪瘟病毒（ASFV）感染引起的一种急性、出血性和严重的传染病。目前，尚无安全有效的药物和疫苗来预防 ASF。挖掘 ASFV 编码的影响 ASFV 毒力和复制的重要蛋白是开发有效疫苗和药物的关键。在这项研究中，发现 ASFV 的 pH240R，一种 ASFV 的衣壳蛋白，抑制了 I 型干扰素（IFN）信号通路。在机制上，pH240R 与 IFNAR1 和 IFNAR2 相互作用，破坏 IFNAR1-TYK2 和 IFNAR2-JAK1 的相互作用。此外，pH240R 抑制 IFN-α诱导的 IFNAR1、TYK2 和 JAK1 的磷酸化，导致 STAT1 和 STAT2 的核内输入和 IFN 刺激基因（ISGs）的表达受到抑制。与这些结果一致，与亲本 ASFV HLJ/18 相比，H240R 缺失的 ASFV（ASFV-∆H240R）感染诱导更多的 ISGs 在猪肺泡巨噬细胞中表达。我们还发现，pH240R 通过抑制 ISGs 表达来增强病毒复制。总之，我们的研究结果阐明，pH240R 通过抑制 JAK-STAT 信号通路增强 ASFV 的复制，这突出了 pH240R 作为潜在药物靶点的可能性。
先天免疫反应是宿主抵御病原体感染的第一道防线，据报道，它会影响非洲猪瘟病毒（ASFV）分离株的复制和毒力。鉴定影响 ASFV 毒力和复制的 ASFV 编码蛋白是开发更有效的疫苗和药物的关键步骤。在这项研究中，我们发现 pH240R 通过破坏 IFNAR1-TYK2 和 IFNAR2-JAK1 的相互作用与 IFNAR1 和 IFNAR2 相互作用，导致干扰素（IFN）刺激基因（ISGs）的表达受到抑制。与这些结果一致，与亲本 ASFV HLJ/18 相比，H240R 缺失的 ASFV（ASFV-∆H240R）感染诱导更多的 ISGs 表达。我们还发现，pH240R 通过抑制 ISGs 的表达来增强病毒复制。总之，我们的研究结果表明，pH240R 通过抑制 IFN-JAK-STAT 轴来增强 ASFV 的复制，这突出了 pH240R 作为潜在药物靶点的可能性。
