P58(IPK): a novel "CIHD" member of the host innate defense response against pathogenic virus infection.
P58(IPK): a novel "CIHD" member of the host innate defense response against pathogenic virus infection.
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DOI：
10.1371/journal.ppat.1000438
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发表时间：
2009-05
期刊：
影响因子：
6.7
通讯作者：
Katze MG
中科院分区：
文献类型：
--
作者：
Goodman AG;Fornek JL;Medigeshi GR;Perrone LA;Peng X;Dyer MD;Proll SC;Knoblaugh SE;Carter VS;Korth MJ;Nelson JA;Tumpey TM;Katze MG
为了支持其复制，病毒利用许多细胞因素和过程。最近的大规模筛查已经识别出数百个此类因素，但人们对病毒如何利用其中任何一个因素知之甚少。流感病毒感染翻译后激活 P58IPK，P58IPK 是干扰素诱导的 dsRNA 激活的 eIF2α 激酶 PKR 的细胞抑制剂。在这里，我们报告 P58IPK 敲除小鼠感染流感病毒导致肺部病理、免疫细胞凋亡、PKR 激活和死亡率增加。对肺转录谱的分析，包括由重建的 1918 年大流行病毒诱导的转录谱分析，揭示了与细胞死亡、免疫和炎症反应相关的基因表达增加。这些实验首次使用哺乳动物感染模型来证明 P58IPK 在抗病毒反应中的作用。我们的结果表明，P58IPK 代表了一类新的分子，即宿主防御的细胞抑制剂 (CIHD)，因为 P58IPK 在病毒感染过程中被激活，抑制病毒诱导的细胞凋亡和炎症，从而延长宿主的生存，甚至同时延长病毒复制。流感病毒引起的呼吸道疾病是美国第七大死因，人们对确定病毒和宿主在感染过程中如何相互作用以及病毒如何引起疾病有很大兴趣。由于流感病毒仅编码八个基因，因此它依赖于细胞蛋白质和新病毒的产生过程。其中一种蛋白质是 P58IPK，长期以来人们一直认为其激活是有效病毒复制所必需的。为了研究 P58IPK 如何影响流感病毒复制和引起疾病的能力，我们感染了缺乏 P58IPK 基因的小鼠品系。我们发现，病毒在缺乏 P58IPK 基因的小鼠中复制同样有效，但这些小鼠更容易受到致命感染。这些小鼠死亡率增加是由于肺部病理变化更大和炎症反应加剧。我们的结果表明，P58IPK 代表了一种新型蛋白质，它通过减少病理学和延长生存期来使宿主受益，尽管它也可能通过允许病毒更长时间地复制而使病毒受益。
To support their replication, viruses take advantage of numerous cellular factors and processes. Recent large-scale screens have identified hundreds of such factors, yet little is known about how viruses exploit any of these. Influenza virus infection post-translationally activates P58IPK, a cellular inhibitor of the interferon-induced, dsRNA-activated eIF2α kinase, PKR. Here, we report that infection of P58IPK knockout mice with influenza virus resulted in increased lung pathology, immune cell apoptosis, PKR activation, and mortality. Analysis of lung transcriptional profiles, including those induced by the reconstructed 1918 pandemic virus, revealed increased expression of genes associated with the cell death, immune, and inflammatory responses. These experiments represent the first use of a mammalian infection model to demonstrate the role of P58IPK in the antiviral response. Our results suggest that P58IPK represents a new class of molecule, a cellular inhibitor of the host defense (CIHD), as P58IPK is activated during virus infection to inhibit virus-induced apoptosis and inflammation to prolong host survival, even while prolonging viral replication. Respiratory illness caused by influenza virus is the seventh leading cause of death in the United States, and there is considerable interest in determining how the virus and host interact during infection and how the virus causes disease. Because influenza virus encodes only eight genes, it is dependent upon cellular proteins and processes for the generation of new viruses. One of these proteins is P58IPK, the activation of which has long been thought to be required for efficient viral replication. To study how P58IPK affects the ability of influenza virus to replicate and cause disease, we infected a strain of mice that lacks the gene for P58IPK. We found that viruses replicated just as efficiently in mice lacking the P58IPK gene, but that these mice were more susceptible to a fatal infection. The increased mortality rate in these mice was due to greater lung pathology and a heightened inflammatory response. Our results show that P58IPK represents a new type of protein that benefits the host by reducing pathology and prolonging survival, even though it may also benefit the virus by allowing it to replicate for a longer period of time.
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影响因子：
5.4
作者：
Kash, JC;Mühlberger, E;Katze, MG
通讯作者：
Katze, MG
影响因子：
64.8
作者：
Kash, John C.;Tumpey, Terrence M.;Katze, Michael G.
通讯作者：
Katze, Michael G.
影响因子：
3.7
作者：
Lee, SB;Rodriguez, D;Esteban, M
通讯作者：
Esteban, M
DOI：
10.1165/rcmb.2002-0055oc
发表时间：
2003-06-01
影响因子：
6.4
作者：
Gern, JE;French, DA;Busse, WW
通讯作者：
Busse, WW
影响因子：
64.8
作者：
Kobasa, Darwyn;Jones, Steven M.;Kawaoka, Yoshihiro
通讯作者：
Kawaoka, Yoshihiro