PKR and RNase L contribute to protection against lethal West Nile Virus infection by controlling early viral spread in the periphery and replication in neurons
PKR and RNase L contribute to protection against lethal West Nile Virus infection by controlling early viral spread in the periphery and replication in neurons
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DOI：
10.1128/jvi.00489-06
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发表时间：
2006-07-01
影响因子：
5.4
通讯作者：
Diamond, Michael S.
中科院分区：
文献类型：
--
作者：
Samuel, Melanie A.;Whitby, Kevin;Diamond, Michael S.
西尼罗河病毒（WNV）是一种嗜神经性、蚊媒传播的黄病毒，可导致致命的脑膜脑炎。I型干扰素（IFN）在控制西尼罗河病毒的复制、传播和嗜性方面起着关键作用。在本研究中，我们开始研究I型干扰素抑制西尼罗河病毒感染的效应机制。缺乏干扰素诱导的双链RNA激活蛋白激酶（PKR）以及2',5'-寡腺苷酸合成酶 - RNase L系统的内切核糖核酸酶的小鼠（PKR - / -×RL - / -）对皮下西尼罗河病毒感染高度易感，其死亡率为90%，而同类野生型小鼠的死亡率为30%。PKR - / -×RL - / -小鼠在其引流淋巴结、血清和脾脏中的病毒载量增加，这导致病毒早期进入中枢神经系统（CNS）以及神经组织中的病毒负荷更高。尽管缺乏RNase L的小鼠显示出更高的中枢神经系统病毒负荷和更高的死亡率，但它们不如PKR - / -×RL - / -小鼠易感；因此，我们也推断PKR在控制西尼罗河病毒感染中具有抗病毒作用。值得注意的是，PKR和RNase L的缺乏导致I型干扰素在原代巨噬细胞和皮质神经元中抑制西尼罗河病毒的能力下降。相比之下，PKR - / -×RL - / -小鼠的颈上神经节外周神经元在干扰素介导的西尼罗河病毒抑制方面没有缺陷。我们的数据表明，PKR和RNase L以细胞受限的方式有助于干扰素介导的保护，并控制外周组织和一些神经元亚型中的西尼罗河病毒感染。
West Nile virus (WNV) is a neurotropic, mosquito-borne flavivirus that can cause lethal meningoencephalitis. Type I interferon (IFN) plays a critical role in controlling WNV replication, spread, and tropism. In this study, we begin to examine the effector mechanisms by which type I IFN inhibits WNV infection. Mice lacking both the interferon-induced, double-stranded-RNA-activated protein kinase (PKR) and the endoribonuclease of the 2',5'-oligoadenylate synthetase-RNase L system (PKR-/- x RL-/-) were highly susceptible to subcutaneous WNV infection, with a 90% mortality rate compared to the 30% mortality rate observed in congenic wild-type mice. PKR-/- x RL-/- mice had increased viral loads in their draining lymph nodes, sera, and spleens, which led to early viral entry into the central nervous system (CNS) and higher viral burden in neuronal tissues. Although mice lacking RNase L showed a higher CNS viral burden and an increased mortality, they were less susceptible than the PKR-/- x RL-/- mice; thus, we also infer an antiviral role for PKR in the control of WNV infection. Notably, a deficiency in both PKR and RNase L resulted in a decreased ability of type I IFN to inhibit WNV in primary macrophages and cortical neurons. In contrast, the peripheral neurons of the superior cervical ganglia of PKR-/- x RL-/- mice showed no deficiency in the IFN-mediated inhibition of WNV. Our data suggest that PKR and RNase L contribute to IFN-mediated protection in a cell-restricted manner and control WNV infection in peripheral tissues and some neuronal subtypes.