Novel strategy for treatment of viral central nervous system infection by using a cell-permeating inhibitor of c-Jun N-terminal kinase
Novel strategy for treatment of viral central nervous system infection by using a cell-permeating inhibitor of c-Jun N-terminal kinase
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DOI：
10.1128/jvi.00467-07
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发表时间：
2007-07-01
影响因子：
5.4
通讯作者：
Tyler, Kenneth L.
中科院分区：
文献类型：
--
作者：
Beckham, J. David;Goody, Robin J.;Tyler, Kenneth L.
病毒性脑炎是世界范围内发病率和死亡率的主要原因，然而，对于大多数中枢神经系统(CNS)病毒感染，还没有被证明有效的治疗方法。许多引起脑炎的病毒在感染后会诱导细胞凋亡并激活c-jun氨基末端激酶(JNK)。我们之前已经证明，呼肠孤病毒感染上皮细胞系激活了JNK依赖的细胞凋亡。我们现在发现呼肠孤病毒感染导致了中枢神经系统中JNK和caspase-3的激活。用竞争性抑制JNK活性的细胞渗透肽治疗Rovinis感染的小鼠，可显著延长T3D(100×501%致死剂量)否则致命攻击后脑内感染小鼠的存活时间。在不改变病毒滴度或病毒抗原分布的情况下，保护与减少中枢神经系统损伤、减少神经元凋亡和减少c-jun激活有关。鉴于该抑制剂在保护小鼠免受病毒性脑炎方面的有效性，JNK抑制代表了一种有前途的新的病毒性脑炎治疗策略。
Viral encephalitis is a major cause of morbidity and mortality worldwide, yet there is no proven efficacious therapy for most viral infections of the central nervous system (CNS). Many of the viruses that cause encephalitis induce apoptosis and activate c-Jun N-terminal kinase (JNK) following infection. We have previously shown that reovirus infection of epithelial cell lines activates JNK-dependent apoptosis. We now show that reovirus infection resulted in activation of JNK and caspase-3 in the CNS. Treatment of reovinis-infected mice with a cell-permeating peptide that competitively inhibits JNK activity resulted in significantly prolonged survival of intracerebrally infected mice following an otherwise lethal challenge with T3D (100 X 501% lethal dose). Protection correlated with reduced CNS injury, reduced neuronal apoptosis, and reduced c-Jun activation without altering the viral titer or viral antigen distribution. Given the efficacy of the inhibitor in protecting mice from viral encephalitis, JNK inhibition represents a promising and novel treatment strategy for viral encephalitis.