Influenza virus infection increases p53 activity: Role of p53 in cell death and viral replication
Influenza virus infection increases p53 activity: Role of p53 in cell death and viral replication
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DOI：
10.1128/jvi.79.14.8802-8811.2005
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发表时间：
2005-07-01
影响因子：
5.4
通讯作者：
Schultz-Cherry, S
中科院分区：
文献类型：
--
作者：
Turpin, E;Luke, M;Schultz-Cherry, S
诱导细胞凋亡是流感病毒感染的一个标志。虽然多种细胞和病毒蛋白参与了这一过程，但到目前为止还没有发现保守的细胞途径。在这项研究中，我们报告了肿瘤抑制蛋白P53在流感病毒感染的细胞中诱导细胞死亡是必不可少的。在原代人类肺细胞中，流感病毒增加了P53蛋白水平。在人类肺细胞系A549中也注意到了这一点，同时上调了P53依赖的基因转录。通过台盼蓝拒染和caspase活性测定，A549细胞中P53活性的降低抑制了流感病毒诱导的细胞死亡。这些发现不是特定于细胞类型的。从p53基因敲除小鼠分离的小鼠胚胎成纤维细胞不存在流感病毒诱导的细胞死亡，而野生型小鼠胚胎成纤维细胞则不是如此，这表明P53是导致流感病毒诱导细胞死亡的常见细胞途径。令人惊讶的是，抑制P53活性会导致病毒复制增加。从机制上讲，这可能是由于P53缺陷细胞中干扰素信号的减少，表明功能性P53参与了对流感感染的干扰素反应。据我们所知，这些研究首次证明P53参与了流感病毒诱导的细胞死亡，抑制P53导致病毒滴度增加，可能是通过调节干扰素反应来实现的。
The induction of apoptotic cell death is a hallmark of influenza virus infection. Although a variety of cellular and viral proteins have been implicated in this process, to date no conserved cellular pathway has been identified. In this study, we report that the tumor suppressor protein p53 is essential for the induction of cell death in influenza virus-infected cells. In primary human lung cells, influenza virus increased p53 protein levels. This was also noted in the human lung cell line A549, along with the up-regulation of p53-dependent gene transcription. Reduction of p53 activity in A549 cells inhibited influenza virus-induced cell death as measured by trypan blue exclusion and caspase activity. These findings were not cell type specific. Influenza virus-induced cell death was absent in mouse embryo fibroblasts isolated from p53 knockout mice, which was not the case in wild-type mouse embryo fibroblasts, suggesting that p53 is a common cellular pathway leading to influenza virus-induced cell death. Surprisingly, inhibiting p53 activity led to elevated virus replication. Mechanistically, this may be due to the decrease in interferon signaling in p53-deficient cells, suggesting that functional p53 is involved in the interferon response to influenza infection. To our knowledge, these are the first studies demonstrating that p53 is involved in influenza virus-induced cell death and that inhibiting p53 leads to increased viral titers, potentially through modulation of the interferon response.