Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses
Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses
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DOI：
10.1128/jvi.00319-15
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发表时间：
2015-06-01
影响因子：
5.4
通讯作者：
Takimoto, Toru
中科院分区：
文献类型：
--
作者：
Hayashi, Tsuyoshi;MacDonald, Leslie A.;Takimoto, Toru
流感病毒感染导致受感染细胞中宿主蛋白质合成的全球抑制。这种宿主关闭被认为允许病毒逃离宿主的抗病毒反应，从而限制病毒的复制和传播。尽管宿主关闭的机制尚不清楚，但通过核糖体移码表达的一种新的病毒蛋白PA-X被发现在流感病毒诱导的宿主关闭中起主要作用。然而，关于PA-X的表达对当前流行的甲型流感病毒致病性和宿主抗病毒反应的影响还知之甚少。在这项研究中，我们拯救了一株重组甲型流感病毒A/California/04/09(H1N1，Cal)，该病毒含有聚合酶PA基因的移码基序突变(CalPA-XFS)。Cal PA-XFS的PA-X表达明显低于Cal野生型(WT)。Cal WT，而不是Cal PA-XFS诱导宿主β-肌动蛋白mRNA的降解并抑制宿主蛋白质合成，支持PA-X通过mRNA衰退诱导宿主关闭的观点。此外，Cal WT比Cal PA-XFS能更快地抑制人呼吸道细胞中β-干扰素的表达和复制。与感染Cal WT的小鼠相比，感染Cal PA-XFS的小鼠的病毒生长水平显著降低，而肺组织中干扰素-βmRNA的表达显著增加。重要的是，感染Cal PA-XFS的小鼠比感染Cal WT的小鼠产生更多的抗血凝素和中和抗体，尽管病毒在肺部的复制水平较低。我们的数据表明，大流行性H1N1病毒的PA-X对病毒的生长和宿主对流感病毒的先天性和获得性免疫反应有强烈的影响。
Influenza virus infection causes global inhibition of host protein synthesis in infected cells. This host shutoff is thought to allow viruses to escape from the host antiviral response, which restricts virus replication and spread. Although the mechanism of host shutoff is unclear, a novel viral protein expressed by ribosomal frameshifting, PA-X, was found to play a major role in influenza virus-induced host shutoff. However, little is known about the impact of PA-X expression on currently circulating influenza A virus pathogenicity and the host antiviral response. In this study, we rescued a recombinant influenza A virus, A/California/04/09 (H1N1, Cal), containing mutations at the frameshift motif in the polymerase PA gene (Cal PA-XFS). Cal PA-XFS expressed significantly less PA-X than Cal wild type (WT). Cal WT, but not Cal PA-XFS, induced degradation of host beta-actin mRNA and suppressed host protein synthesis, supporting the idea that PA-X induces host shutoff via mRNA decay. Moreover, Cal WT inhibited beta interferon (IFN-beta) expression and replicated more rapidly than Cal PA-XFS in human respiratory cells. Mice infected with Cal PA-XFS had significantly lower levels of viral growth and greater expression of IFN-beta mRNA in their lungs than mice infected with Cal WT. Importantly, more antihemagglutinin and neutralizing antibodies were produced in Cal PA-XFS-infected mice than in Cal WT-infected mice, despite the lower level of virus replication in the lungs. Our data indicate that PA-X of the pandemic H1N1 virus has a strong impact on viral growth and the host innate and acquired immune responses to influenza virus.