Caspase 3-dependent cell death of neurons contributes to the pathogenesis of West Nile virus encephalitis
Caspase 3-dependent cell death of neurons contributes to the pathogenesis of West Nile virus encephalitis
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DOI：
10.1128/jvi.02311-06
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发表时间：
2007-03-01
影响因子：
5.4
通讯作者：
Diamond, Michael S.
中科院分区：
文献类型：
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作者：
Samuel, Melanie A.;Morrey, John D.;Diamond, Michael S.
西尼罗河病毒(WNV)是一种嗜神经的节肢动物传播的黄病毒，已成为病毒性脑炎的重要全球病因。为了探讨西尼罗河病毒诱导神经元死亡的机制以及细胞凋亡在发病机制中的重要性，我们评估了关键的凋亡调节因子caspase3的作用。西尼罗河病毒感染诱导了野生型小鼠脑内caspase3的激活和凋亡。值得注意的是，同源caspase 3(-/-)小鼠对致死性西尼罗河病毒感染的抵抗力更强，尽管在组织病毒载量或病毒传播动力学方面没有显著差异。相反，在caspase 3(-/-)小鼠的大脑皮层、脑干和小脑中观察到神经元死亡减少。同样，西尼罗河病毒感染后，原代中枢神经系统(CNS)来源的神经元显示caspase 3激活和凋亡，用caspase抑制剂或caspase 3基因缺陷治疗可显著减少病毒诱导的死亡。这些研究证实caspase3依赖的细胞凋亡参与了致死性WNV脑炎的发病机制，并提出了限制中枢神经系统损伤的可能的新的治疗靶点。
West Nile virus (WNV) is a neurotropic, arthropod-borne flavivirus that has become a significant global cause of viral encephalitis. To examine the mechanisms of WNV-induced neuronal death and the importance of apoptosis in pathogenesis, we evaluated the role of a key apoptotic regulator, caspase 3. WNV infection induced caspase 3 activation and apoptosis in the brains of wild-type mice. Notably, congenic caspase 3(-/-) mice were more resistant to lethal WNV infection, although there were no significant differences in the tissue viral burdens or the kinetics of viral spread. Instead, decreased neuronal death was observed in the cerebral cortices, brain stems, and cerebella of caspase 3(-/-) mice. Analogously, primary central nervous system (CNS)-derived neurons demonstrated caspase 3 activation and apoptosis after WNV infection, and treatment with caspase inhibitors or a genetic deficiency in caspase 3 significantly decreased virus-induced death. These studies establish that caspase 3-dependent apoptosis contributes to the pathogenesis of lethal WNV encephalitis and suggest possible novel therapeutic targets to restrict CNS injury.