A Critical Determinant of Neurological Disease Associated with Highly Pathogenic Tick-Borne Flavivirus in Mice
A Critical Determinant of Neurological Disease Associated with Highly Pathogenic Tick-Borne Flavivirus in Mice
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DOI：
10.1128/jvi.00421-14
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发表时间：
2014-05-01
影响因子：
5.4
通讯作者：
Takashima, Ikuo
中科院分区：
文献类型：
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作者：
Yoshii, Kentaro;Sunden, Yuji;Takashima, Ikuo
蜱传脑炎病毒（TBEV）和鄂木斯克出血热病毒（OHFV）是高致病性蜱传黄病毒; TBEV导致人类神经系统疾病，而OHFV导致通常与出血热鉴别的疾病。虽然TBEV和OHFV在遗传上密切相关，但导致这些不同疾病表型的病毒决定因素尚未确定。在这项研究中，嵌合病毒的TBEV和OHFV的组成部分，采用感染性克隆技术产生，并在小鼠模型中分析其病理特征，以确定病毒特异性疾病的决定因素。我们发现，NS 5蛋白C末端附近只有四个氨基酸主要负责神经系统疾病的发展。这四种氨基酸的突变对小鼠的病毒复制或组织病理学特征（包括炎症反应）没有影响。这些发现表明NS 5在TBEV感染后刺激神经元功能障碍和变性中起关键作用，并为蜱传黄病毒发病机制的分子机制提供了新的见解。
Tick-borne encephalitis virus (TBEV) and Omsk hemorrhagic fever virus (OHFV) are highly pathogenic tick-borne flaviviruses; TBEV causes neurological disease in humans, while OHFV causes a disease typically identified with hemorrhagic fever. Although TBEV and OHFV are closely related genetically, the viral determinants responsible for these distinct disease phenotypes have not been identified. In this study, chimeric viruses incorporating components of TBEV and OHFV were generated using infectious clone technology, and their pathological characteristics were analyzed in a mouse model to identify virus-specific determinants of disease. We found that only four amino acids near the C terminus of the NS5 protein were primarily responsible for the development of neurological disease. Mutation of these four amino acids had no effect on viral replication or histopathological features, including inflammatory responses, in mice. These findings suggest a critical role for NS5 in stimulating neuronal dysfunction and degeneration following TBEV infection and provide new insights into the molecular mechanisms underlying the pathogenesis of tick-borne flaviviruses.