TNF-α acts as an immunoregulator in the mouse brain by reducing the incidence of severe disease following Japanese encephalitis virus infection.
TNF-α acts as an immunoregulator in the mouse brain by reducing the incidence of severe disease following Japanese encephalitis virus infection.
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DOI：
10.1371/journal.pone.0071643
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Morita K
中科院分区：
文献类型：
--
作者：
Hayasaka D;Shirai K;Aoki K;Nagata N;Simantini DS;Kitaura K;Takamatsu Y;Gould E;Suzuki R;Morita K
日本脑炎病毒（JEV）引起人类急性中枢神经系统（CNS）疾病，其临床症状从发热性疾病到脑膜炎和脑炎不等。然而，严重脑炎的发病机制尚未完全阐明。在这项研究中，我们使用小鼠模型研究了与致死性乙脑病毒感染相关的发病机制。在神经外感染JEV JaOArS982株后，感染小鼠表现出从轻微到致命的临床症状。比较重度和轻度感染jaaars982小鼠的发病反应，发现重度感染小鼠大脑中TNF-α水平升高。但出乎意料的是，TNF-α KO小鼠的死亡率较WT小鼠明显升高，表明TNF-α对致死性感染具有保护作用。有趣的是，WT和TNF-α KO小鼠的中枢神经系统病毒载量没有显著差异。然而，在TNF-α KO小鼠的中枢神经系统中观察到夸张的炎症反应。虽然在IL-10 KO小鼠中也得到了这些观察结果，但TNF-α KO小鼠的死亡率和炎症反应增强更为明显。因此，我们的研究结果提供了第一个证据，证明TNF-α在乙脑病毒感染期间对中枢神经系统中的促炎细胞因子具有免疫调节作用，从而保护动物免受致命疾病的侵害。因此，我们认为，严重病例中TNF-α水平升高是严重疾病的结果，其次，免疫病理作用导致严重的神经元变性导致致命疾病。未来，进一步阐明TNF-α的免疫调节机制将是制定有效的日本脑炎治疗策略的重要优先事项。
Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.
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影响因子：
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作者：
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通讯作者：
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