The NS5 Protein of the Virulent West Nile Virus NY99 Strain Is a Potent Antagonist of Type I Interferon-Mediated JAK-STAT Signaling
The NS5 Protein of the Virulent West Nile Virus NY99 Strain Is a Potent Antagonist of Type I Interferon-Mediated JAK-STAT Signaling
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DOI：
10.1128/jvi.01161-09
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发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Best, Sonja M.
中科院分区：
文献类型：
--
作者：
Laurent-Rolle, Maudry;Boer, Elena F.;Best, Sonja M.
由节肢动物传播的黄病毒对人类造成巨大的疾病负担，每年造成数百万人感染。迄今为止研究的所有媒介传播黄病毒通过抑制α/β干扰素（IFN-α/β）介导的JAK-STAT信号转导来抑制宿主对感染的先天性应答。一些黄病毒的病毒非结构蛋白NS 5作为主要的IFN拮抗剂起作用，与IFN依赖性STAT 1磷酸化（pY-STAT 1）的抑制或与STAT 2降解相关。西尼罗河病毒（WNV）感染阻止pY-STAT 1，尽管WNV NS 5在IFN拮抗作用中的作用尚未完全探索。在这里，我们报告说，NS 5从毒力NY 99株西尼罗河病毒防止pY-STAT 1积累，抑制IFN依赖性基因的表达，并挽救了IFN敏感性高的病毒（纽卡斯尔病病毒）在IFN的存在下的生长，这表明这种蛋白质可以作为一个有效的IFN拮抗剂。相反，来自昆津病毒（Kunjin virus，KUN）（WNV的一种天然减毒亚型）的NS 5是pY-STAT 1的弱抑制剂。KUN NS 5中的单个残基突变为WNV-NY 99 NS 5中的类似残基（S653 F）使得KUN NS 5成为pY-STAT 1的有效抑制剂。将该突变并入重组KUN中导致JAK-STAT信号传导的抑制比野生型病毒大30倍，并且在IFN存在下增强KUN复制。因此，自然发生的突变与NS 5在IFN拮抗作用中的功能相关，并可能影响WNV田间分离株的毒力。
Flaviviruses transmitted by arthropods represent a tremendous disease burden for humans, causing millions of infections annually. All vector-borne flaviviruses studied to date suppress host innate responses to infection by inhibiting alpha/beta interferon (IFN-alpha/beta)-mediated JAK-STAT signal transduction. The viral nonstructural protein NS5 of some flaviviruses functions as the major IFN antagonist, associated with inhibition of IFN-dependent STAT1 phosphorylation (pY-STAT1) or with STAT2 degradation. West Nile virus (WNV) infection prevents pY-STAT1 although a role for WNV NS5 in IFN antagonism has not been fully explored. Here, we report that NS5 from the virulent NY99 strain of WNV prevented pY-STAT1 accumulation, suppressed IFN-dependent gene expression, and rescued the growth of a highly IFN-sensitive virus (Newcastle disease virus) in the presence of IFN, suggesting that this protein can function as an efficient IFN antagonist. In contrast, NS5 from Kunjin virus (KUN), a naturally attenuated subtype of WNV, was a poor suppressor of pY-STAT1. Mutation of a single residue in KUN NS5 to the analogous residue in WNV-NY99 NS5 (S653F) rendered KUN NS5 an efficient inhibitor of pY-STAT1. Incorporation of this mutation into recombinant KUN resulted in 30-fold greater inhibition of JAK-STAT signaling than with the wild-type virus and enhanced KUN replication in the presence of IFN. Thus, a naturally occurring mutation is associated with the function of NS5 in IFN antagonism and may influence virulence of WNV field isolates.