Inhibition of interferon induction and action by the nairovirus Nairobi sheep disease virus/Ganjam virus.

Inhibition of interferon induction and action by the nairovirus Nairobi sheep disease virus/Ganjam virus.
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DOI:
10.1371/journal.pone.0028594
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发表时间:
2011
期刊:
影响因子:
3.7
通讯作者:
Baron MD
Baron MD
中科院分区:
综合性期刊3区
文献类型:
--
作者:
Holzer B;Bakshi S;Bridgen A;Baron MD

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奈洛病毒是一组重要的蜱传病毒,包括人(克里米亚刚果出血热病毒)和牲畜(杜格布病毒、奈洛比绵羊病病毒)的病原体。NSDV在东非和印度次大陆的大部分地区发现(在那里它被称为Ganjam病毒)。我们已经研究了NSDV对抗干扰素诱导和作用的能力。致病性和致病性分离株均能积极抑制1型干扰素的诱导,并阻断1型和2型干扰素的信号通路。利用病毒蛋白或病毒蛋白片段的瞬时表达,这些活性都映射到病毒RNA聚合酶中发现的卵巢肿瘤样蛋白酶结构域(OTU)。病毒感染或转染细胞中该OTU结构域的表达,导致宿主细胞蛋白中泛素或ISG15蛋白的掺入量大幅减少。OTU中的点突变抑制了蛋白酶的活性,也阻止了它对抗干扰素的诱导和作用。有趣的是,外周位点的突变对OTU抑制泛素化和ISG15化的能力几乎没有明显影响,但却消除了OTU阻断1型干扰素诱导和2型干扰素作用的能力,但对阻断1型干扰素作用的能力的影响较小,这表明除泛素和ISG15之外的靶点可能参与了病毒OTU的作用。
The Nairoviruses are an important group of tick-borne viruses that includes pathogens of man (Crimean Congo hemorrhagic fever virus) and livestock animals (Dugbe virus, Nairobi sheep disease virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.
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