Inhibition of IRF-3 activation by VP35 is critical for the high level of virulence of ebola virus
Inhibition of IRF-3 activation by VP35 is critical for the high level of virulence of ebola virus
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DOI：
10.1128/jvi.02344-07
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发表时间：
2008-03-01
影响因子：
5.4
通讯作者：
Nichol, Stuart T.
中科院分区：
文献类型：
--
作者：
Hartman, Amy L.;Bird, Brian H.;Nichol, Stuart T.
扎伊尔埃博拉病毒引起一种进展迅速的出血性疾病，死亡率高。确定导致埃博拉病毒引起的疾病严重程度的病毒毒力因素对于设计针对该疾病的治疗方法和疫苗至关重要。鉴于疾病进展迅速，病毒在感染过程早期与先天免疫系统的相互作用可能在决定疾病的结果中起着重要作用。埃博拉病毒VP35蛋白抑制IRF-3的激活，IRF-3是诱导早期抗病毒免疫的关键转录因子。先前的研究表明，VP35中的单个氨基酸变化（R312A）使该蛋白无法抑制IRF-3的激活。产生了一种反向遗传产生的、小鼠适应的重组埃博拉病毒，该病毒编码VP35中的R312A突变。我们发现，相对于含有真实VP35序列的野生型病毒，VP35中单个氨基酸的改变使病毒在小鼠中完全减毒。鉴于这些病毒在VP35的IRF-3抑制域中只有一个氨基酸的差异，毒力的改变水平是显著的，并突出了VP35在埃博拉病毒发病机制中的重要性。
Zaire ebolavirus causes a rapidly progressing hemorrhagic disease with high mortality. Identification of the viral virulence factors that contribute to the severity of disease induced by Ebola virus is critical for the design of therapeutics and vaccines against the disease. Given the rapidity of disease progression, virus interaction with the innate immune system early in the course of infection likely plays an important role in determining the outcome of the disease. The Ebola virus VP35 protein inhibits the activation of IRF-3, a critical transcription factor for the induction of early antiviral immunity. Previous studies revealed that a single amino acid change (R312A) in VP35 renders the protein unable to inhibit IRF-3 activation. A reverse-genetics-generated, mouse-adapted, recombinant Ebola virus that encodes the R312A mutation in VP35 was produced. We found that relative to the case for wild-type virus containing the authentic VP35 sequence, this single amino acid change in VP35 renders the virus completely attenuated in mice. Given that these viruses differ by only a single amino acid in the IRF-3 inhibitory domain of VP35, the level of alteration of virulence is remarkable and highlights the importance of VP35 for the pathogenesis of Ebola virus.