A single siRNA suppresses fatal encephalitis induced by two different flaviviruses.
A single siRNA suppresses fatal encephalitis induced by two different flaviviruses.
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DOI：
10.1371/journal.pmed.0030096
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发表时间：
2006-04
期刊：
影响因子：
15.8
通讯作者：
Manjunath N
中科院分区：
文献类型：
--
作者：
Kumar P;Lee SK;Shankar P;Manjunath N
日本脑炎病毒（JEV）和西尼罗河病毒（WNV）是嗜神经黄病毒，可引起急性脑炎，病死率高。目前还没有有效的治疗这些感染。我们测试了基于RNA干扰（RNAi）的干预以抑制小鼠中的致死性乙脑和WN脑炎。为了诱导RNAi，我们使用慢病毒表达的短发夹RNA（shRNA）或合成的短干扰RNA（siRNA）。作为靶标，我们选择了病毒包膜蛋白的结构域II中的cd环编码序列，该序列在所有黄病毒中高度保守，因为其在膜融合中起重要作用。使用CD环中仅在JEV或WNV的不同毒株中保守的物种特异性序列作为靶标，我们可以实现针对相应病毒的特异性保护。然而，通过靶向cd环内的跨物种保守序列，我们能够保护小鼠免受两种病毒引起的脑炎。在病毒攻击前或病毒攻击后进行siRNA治疗，单次颅内给予慢病毒递送的shRNA或脂质复合物siRNA足以预防致死性脑炎。基于RNAi的干预在小鼠中提供了几乎完全的保护以免受JEV和WNV诱导的脑炎。我们的研究结果表明，据我们所知，siRNA可以作为一种广谱抗病毒剂用于治疗由多种相关病毒引起的脑炎。向小鼠颅内施用慢病毒递送的短发夹RNA或脂质复合的短干扰RNA提供针对致死性黄病毒脑炎的保护。
Japanese encephalitis virus (JEV) and West Nile virus (WNV) are neurotropic flaviviruses that can cause acute encephalitis with a high fatality rate. Currently there is no effective treatment for these infections. We tested RNA interference (RNAi)-based intervention to suppress lethal JE and WN encephalitis in mice. To induce RNAi, we used either lentivirally expressed short hairpin RNA (shRNA) or synthetic short interfering RNA (siRNA). As target, we selected the cd loop-coding sequence in domain II of the viral Envelope protein, which is highly conserved among all flaviviruses because of its essential role in membrane fusion. Using as a target a species-specific sequence in the cd loop that is conserved only among the different strains of either JEV or WNV, we could achieve specific protection against the corresponding virus. However, by targeting a cross-species conserved sequence within the cd loop, we were able to protect mice against encephalitis induced by both viruses. A single intracranial administration of lentivirally delivered shRNA or lipid-complexed siRNA before viral challenge or siRNA treatment after viral challenge was sufficient for protection against lethal encephalitis. RNAi-based intervention affords near complete protection from both JEV- and WNV- induced encephalitis in mice. Our results show, to our knowledge for the first time, that siRNA can be used as a broad-spectrum antiviral agent for treating encephalitis caused by multiple related viruses. Intracranial administration to mice of lentivirally delivered short hairpin RNA or lipid-complexed short interfering RNA provides protection against lethal flavivirus encephalitis.
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