Multiple anti-interferon actions of the influenza A virus NS1 protein
Multiple anti-interferon actions of the influenza A virus NS1 protein
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DOI：
10.1128/jvi.02581-06
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发表时间：
2007-07-01
影响因子：
5.4
通讯作者：
Martinez-Sobrido, Luis
中科院分区：
文献类型：
--
作者：
Kochs, Georg;Garcia-Sastre, Adolfo;Martinez-Sobrido, Luis
甲型流感病毒（FLUAV）的复制和致病性部分由α/β干扰素（IFN-α/β）系统控制。这种病毒-宿主相互作用依赖于IFN-α/β的产生和病毒非结构蛋白NS 1对抗IFN系统的能力。已经描述了NS 1的两种不同机制，即阻断IFN调节因子3（IRF 3）的活化和阻断细胞mRNA的转录后加工。在这里，我们直接比较NS 1基因产物的能力，从三个不同的人流感病毒（H1N1）株，以抵消抗病毒宿主反应。我们发现A/PR/8/34 NS 1具有很强的抑制IRF 3和IFN-β启动子激活的能力，但不能抑制其他细胞基因的表达。相比之下，导致西班牙流感大流行的病毒A/Tx/36/91和A/BM/1/18的NS 1蛋白引起额外的细胞基因表达的抑制。因此，这些NS 1蛋白阻止了IFN诱导的抗病毒状态的建立，即使在IFN存在下也允许病毒复制。有趣的是，基因表达的阻断依赖于一个新描述的NS 1结构域，该结构域对于与细胞前mRNA加工机制的切割和多聚腺苷酸化特异性因子（CPSF）组分的相互作用很重要，但在A/PR/8/34 NS 1中没有功能。我们鉴定了NS 1中的Phe-103和Met-106残基以及先前描述的C-末端结合结构域对于CPSF结合至关重要。我们的研究结果表明FLUAV NS 1能够在多个水平上抑制抗病毒宿主防御，并且存在可能调节病毒致病性的菌株特异性差异。
The replication and pathogenicity of influenza A virus (FLUAV) are controlled in part by the alpha/beta interferon (IFN-alpha/beta) system. This virus-host interplay is dependent on the production of IFN-alpha/beta and on the capacity of the viral nonstructural protein NS1 to counteract the IFN system. Two different mechanisms have been described for NS1, namely, blocking the activation of IFN regulatory factor 3 (IRF3) and blocking posttranscriptional processing of cellular mRNAs. Here we directly compare the abilities of NS1 gene products from three different human FLUAV (H1N1) strains to counteract the antiviral host response. We found that A/PR/8/34 NS1 has a strong capacity to inhibit IRF3 and activation of the IFN-beta promoter but is unable to suppress expression of other cellular genes. In contrast, the NS1 proteins of A/Tx/36/91 and of A/BM/1/18, the virus that caused the Spanish influenza pandemic, caused suppression of additional cellular gene expression. Thus, these NS1 proteins prevented the establishment of an IFN-induced antiviral state, allowing virus replication even in the presence of IFN. Interestingly, the block in gene expression was dependent on a newly described NS1 domain that is important for interaction with the cleavage and polyadenylation specificity factor (CPSF) component of the cellular pre-mRNA processing machinery but is not functional in A/PR/8/34 NS1. We identified the Phe-103 and Met-106 residues in NS1 as being critical for CPSF binding, together with the previously described C-terminal binding domain. Our results demonstrate the capacity of FLUAV NS1 to suppress the antiviral host defense at multiple levels and the existence of strain-specific differences that may modulate virus pathogenicity.