Stewart Michael J, Blum Mary Ann, Sherry Barbara
Department of Microbiology, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC 27606, USA.
Virology. 2003 Sep 15;314(1):92-100. doi: 10.1016/s0042-6822(03)00414-8.
Reovirus-induced murine myocarditis provides an excellent model for the human disease. Previously, we showed that reovirus induction of and sensitivity to interferon-beta (IFN-beta) are important determinants of protection against cardiac damage. IFN-beta 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-2 alpha (eIF2 alpha) leading to the cessation of host cell translation. Additionally, activated PKR can exert its antiviral effects by inducing phosphorylation of I kappa B, leading to the activation of the transcription factor NF kappa B and subsequent induction of IFN-beta. Thus, activated PKR can both induce and be induced by IFN-beta. 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-beta 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.
呼肠孤病毒诱导的小鼠心肌炎为人类疾病提供了一个极佳的模型。此前，我们发现呼肠孤病毒对β干扰素（IFN-β）的诱导及敏感性是预防心脏损伤的重要决定因素。IFN-β可诱导多种具有抗病毒活性的基因，包括双链RNA激活蛋白激酶PKR。PKR一旦与病毒双链RNA结合就会被激活，并使真核起始因子2α（eIF2α）磷酸化，从而导致宿主细胞翻译停止。此外，激活的PKR可通过诱导IκB磷酸化发挥抗病毒作用，导致转录因子NF-κB激活及随后IFN-β的诱导。因此，激活的PKR既能被IFN-β诱导，也能诱导IFN-β。最近，大量报道表明PKR对于IFN的诱导以及疾病预防均非必需。然而，PKR在心脏对病毒感染的反应中的作用及其预防心脏损伤的能力在很大程度上尚未得到探索。在此，我们证明PKR对于原代心肌细胞培养中病毒诱导IFN-β至关重要。此外，我们表明PKR缺失会导致心肌炎型和非心肌炎型呼肠孤病毒的毒力增加。最后，我们证明PKR对于预防呼肠孤病毒诱导的病毒性心肌炎至关重要。
