Scheuner Donalyn, Gromeier Matthias, Davies Monique V, Dorner Andrew J, Song Benbo, Patel Rupali V, Wimmer Eckard J, McLendon Roger E, Kaufman Randal J
Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Virology. 2003 Dec 20;317(2):263-74. doi: 10.1016/j.virol.2003.08.010.
The double-stranded (ds) RNA-activated protein kinase (PKR) plays an important role in control of viral infections and cell growth. We have studied the role of PKR in viral infection in mice that are defective in the PKR signaling pathway. Transgenic mice were derived that constitutively express a trans-dominant-negative kinase-defective mutant PKR under control of the beta-actin promoter. The trans-dominant-negative PKR mutant expressing transgenic mice do not have a detectable phenotype, similar to observations with PKR knock-out mice. The requirement for PKR in viral pathogenesis was studied by intracerebral infection of mice with a mouse-adapted poliovirus. Histopathological analysis revealed diffuse encephalomyelitis with severe inflammatory lesions throughout the central nervous system (CNS) in infected wild-type mice. In contrast, histopathological evaluation of virus-injected trans-dominant-negative PKR transgenic mice as well as PKR knock-out mice yielded no signs of tissue damage associated with inflammatory host responses. However, the virus did replicate in both models of PKR-deficient mice at a level equal to that observed in wild-type infected mice. Although the results indicate a clear difference in susceptibility to poliovirus-induced encephalitis, this difference manifests clinically as a slight delay in fatal neuropathy in trans-dominant-negative PKR transgenic and PKR knock-out animals. Our observations support the finding that viral-induced PKR activation may play a significant role in pathogenesis by mediating the host response to viral CNS infection. They support PKR to be an effective target to control tissue damage due to deleterious host responses to viral infection.
双链（ds）RNA激活蛋白激酶（PKR）在控制病毒感染和细胞生长中发挥着重要作用。我们研究了PKR在PKR信号通路缺陷的小鼠病毒感染中的作用。构建了转基因小鼠，其在β-肌动蛋白启动子的控制下组成性表达一种反式显性负性激酶缺陷型突变体PKR。表达反式显性负性PKR突变体的转基因小鼠没有可检测到的表型，这与PKR基因敲除小鼠的观察结果相似。通过用小鼠适应的脊髓灰质炎病毒脑内感染小鼠，研究了PKR在病毒发病机制中的需求。组织病理学分析显示，感染的野生型小鼠整个中枢神经系统（CNS）出现弥漫性脑脊髓炎并伴有严重炎症病变。相比之下，对注射病毒的反式显性负性PKR转基因小鼠以及PKR基因敲除小鼠的组织病理学评估未发现与炎症宿主反应相关的组织损伤迹象。然而，病毒在两种PKR缺陷小鼠模型中的复制水平与在野生型感染小鼠中观察到的水平相当。尽管结果表明对脊髓灰质炎病毒诱导的脑炎的易感性存在明显差异，但这种差异在临床上表现为反式显性负性PKR转基因和PKR基因敲除动物致命性神经病变的轻微延迟。我们的观察结果支持以下发现：病毒诱导的PKR激活可能通过介导宿主对病毒性CNS感染的反应在发病机制中发挥重要作用。它们支持PKR成为控制因宿主对病毒感染的有害反应而导致的组织损伤的有效靶点。
