J Virol:农科院哈兽研所仇华吉研究员发现新抗猪瘟病毒分子

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近日，国际著名病毒学杂志《Journal of Virology》上在线发表中国农业科学院哈尔滨兽医研究所猪烈性传染病创新团队仇华吉研究员的一篇研究论文，团队经过系统研究发现了一个具有抗猪瘟病毒活性的干扰素刺激基因(ISG)即鸟苷酸结合蛋白1(GBP1)，并阐明了其抗病毒机制。此项研究发现，不仅有助于深入了解宿主抗病毒机理，同时也为揭示猪瘟病毒逃避宿主抗病毒策略提供了线索。此外，抗病毒ISG研究对创新猪瘟防控策略具有重要意义，并为猪瘟病毒所在的黄病毒科其它成员的抗病毒研究提供了参考。

猪瘟是猪的一种急性高度接触性传染病，其传播快、致死率高，常造成重大经济损失，严重威胁世界养猪业，被世界动物卫生组织(OIE)列入须申报的动物疫病名录，我国在国家中长期动物疫病防治规划中将其列为优先防治的一类动物疫病之一。

ISG是宿主发挥抗病毒作用的一类效应分子，其几乎可以靶向病毒复制周期的每一个环节，包括侵入、脱壳、基因组复制、病毒粒子装配以及释放等，通过阻断病毒复制周期的某一环节，从而抑制病毒在机体内的存活。因此，研究ISG对于抗病毒感染具有重要意义。

仇华吉表示科研人员利用报告病毒并结合过表达细胞系的高通量筛选策略，获得了多个抗猪瘟病毒ISG候选分子，经过系统的鉴定，证实GBP1 为抗猪瘟病毒的ISG，该分子发挥抗病毒作用依赖其GTPase活性，而猪瘟病毒则利用其NS5A蛋白与GBP1相互作用抑制GBP1的GTPase活性，进而拮抗了GBP1的抗病毒功能。

据悉，该团队还在国际知名期刊抗病毒研究《Antiviral Research》上创新性地利用RNA干扰技术结合报告病毒进行高通量筛选，鉴定了OAS1等多个具有抗猪瘟病毒活性的新ISG。

原文链接：

Guanylate-binding protein 1, an interferon-induced GTPase, exerts an antiviral activity against classical swine fever virus depending on its GTPase activity

原文摘要：

Many viruses trigger the type I interferon (IFN) pathway upon infection, resulting in the transcription of hundreds of interferon-stimulated genes (ISGs), which define the antiviral state of the host. Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), a highly contagious viral disease endangering the pig industry in many countries. However, anti-CSFV ISGs are poorly documented. Here, we screened 20 ISGs that are commonly induced by type I IFNs against CSFV in lentivirus-delivered cell lines, resulting in the identification of guanylate-binding protein 1 (GBP1) as a potent anti-CSFV ISG. We observed that overexpression of GBP1, an IFN-induced GTPase, remarkably suppressed CSFV replication, whereas knocking down the endogenous GBP1 expression by small interfering RNAs significantly promoted CSFV growth. Furthermore, we demonstrated that GBP1 acted mainly upon the early phase of CSFV replication and inhibited the translation efficiency of the internal ribosome entry site of CSFV. In addition, we found that GBP1 was upregulated at the transcriptional level in CSFV-infected PK-15 cells and in various organs of CSFV-infected pigs. Coimmunoprecipitation and GST pulldown assays revealed that GBP1 interacted with the NS5A protein of CSFV and this interaction was mapped in the N-terminal globular GTPase domain of GBP1. Interestingly, the K51 of GBP1, which is crucial for its GTPase activity, was essential for the inhibition of CSFV replication. We further showed that NS5A-GBP1 interaction inhibited GTPase activity, which was critical for its antiviral effect. Taken together, GBP1 is an anti-CSFV ISG whose action depends on its GTPase activity.

doi:10.1128/JVI.02718-15


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