PKR's protective role in viral myocarditis.
PKR's protective role in viral myocarditis.
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DOI：
10.1016/s0042-6822(03)00414-8
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发表时间：
2003-09
期刊：
影响因子：
3.7
通讯作者：
Michael J. Stewart;M. A. Blum;B. Sherry
中科院分区：
文献类型：
--
作者：
Michael J. Stewart;M. A. Blum;B. Sherry
呼肠孤病毒诱导的小鼠心肌炎为人类疾病提供了一个很好的模型。在此之前，我们已经证明呼肠孤病毒对干扰素-β(干扰素-β)的诱导和敏感性是保护心脏免受损伤的重要决定因素。干扰素-β可诱导一系列具有抗病毒活性的基因，包括双链RNA激活的蛋白激酶。一旦与病毒dsRNA结合，PKR被激活并磷酸化真核细胞起始因子-2α(eIF2α)，导致宿主细胞停止翻译。此外，活化的PKR可以通过诱导I-κB的磷酸化，导致转录因子NF-κB的激活，从而诱导干扰素-β，从而发挥其抗病毒作用。因此，活化的PKR既可以诱导，也可以被干扰素-β诱导。最近，许多报道表明，PKR在诱导干扰素和预防疾病方面都是必不可少的。然而，PKR在应对病毒感染时在心脏中的作用以及它预防心脏损伤的能力在很大程度上还没有被探索。在这里，我们证明了在病毒诱导干扰素-β在原代培养的心肌细胞中，PKR是关键的。此外，我们还发现PKR的缺失会导致心肌型和非心肌型呼肠孤病毒毒力的增加。最后，我们证明了PKR对于预防呼肠孤病毒引起的病毒性心肌炎是至关重要的。
Reovirus-induced murine myocarditis provides an excellent model for the human disease. Previously, we showed that reovirus induction of and sensitivity to interferon-β (IFN-β) are important determinants of protection against cardiac damage. IFN-β induces a number of genes with antiviral activities, including the dsRNA-activated protein kinase, PKR. Once bound to viral dsRNA, PKR becomes activated and phosphorylates eukaryotic initiation factor-2α (eIF2α) leading to the cessation of host cell translation. Additionally, activated PKR can exert its antiviral effects by inducing phosphorylation of IκB, leading to the activation of the transcription factor NFκB and subsequent induction of IFN-β. Thus, activated PKR can both induce and be induced by IFN-β. Recently, numerous reports have shown PKR to be dispensable for both induction of IFN as well as protection against disease. However, both PKR's role in the heart in response to viral infection and its ability to prevent cardiac damage have gone largely unexplored. Here, we demonstrate PKR to be critical for viral induction of IFN-β in primary cardiac myocyte cultures. Additionally, we show that loss of PKR leads to an increase in virulence for both myocarditic and nonmyocarditic reoviruses. Finally, we demonstrate PKR to be critical for protection against reovirus-induced viral myocarditis.