Tick-borne encephalitis virus induces chemokine RANTES expression via activation of IRF-3 pathway.
Tick-borne encephalitis virus induces chemokine RANTES expression via activation of IRF-3 pathway.
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蜱传脑炎病毒通过激活IRF-3途径诱导趋化因子RANTES表达
DOI：
10.1186/s12974-016-0665-9
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发表时间：
2016-08-30
影响因子：
9.3
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Zhang X;Zheng Z;Liu X;Shu B;Mao P;Bai B;Hu Q;Luo M;Ma X;Cui Z;Wang H
蜱传脑炎病毒（Tick-borne encephalitis virus，TBEV）是一种以中枢神经系统（central nervous system，CNS）为靶点的重要黄病毒，可引起人类脑炎。虽然神经炎症机制可能有助于脑组织的破坏，诱导途径和特定的趋化因子在TBEV介导的神经系统疾病的潜在作用知之甚少。MethodsBALB/c小鼠脑内注射TBEV，然后通过评估趋化因子和细胞因子的档案，使用蛋白质阵列分析。用CC趋化因子拮抗剂Met-RANTES或抗RANTES mAb治疗病毒感染的小鼠，以确定RANTES在影响TBEV诱导的神经系统疾病中的作用。使用RANTES启动子荧光素酶报告分析，siRNA介导的敲低，和药理学抑制剂在人脑衍生的细胞culture models.ResultsIn小鼠模型，病理特征，包括显着的炎性细胞浸润中观察到脑切片，这与一个强大的上调RANTES脑内，但不是在外周组织和血清中的潜在信号转导机制进行了描绘。在CNS内拮抗RANTES延长了小鼠的存活时间，并减少了TBEV感染后脑中浸润细胞的积累。通过体外研究，我们发现，病毒感染上调RANTES生产在mRNA和蛋白质水平的人脑源性细胞系和初级祖细胞源性星形胶质细胞。此外，IRF-3途径似乎是TBEV诱导的RANTES产生所必需的。IRF-3结合基序的位点突变废除了病毒感染脑细胞中RANTES启动子的活性。此外，IRF-3被激活后TBEV感染的TBK 1和IRF-3的磷酸化证明，而IRF-3的激活的封锁大大降低病毒诱导的RANTES expressions.ConclusionsOur研究结果一起提供深入了解的分子机制，潜在的RANTES生产TBEV诱导，突出其在神经炎症反应的过程中TBEV感染的重要性。
BackgroundTick-borne encephalitis virus (TBEV) is one of the most important flaviviruses that targets the central nervous system (CNS) and causes encephalitides in humans. Although neuroinflammatory mechanisms may contribute to brain tissue destruction, the induction pathways and potential roles of specific chemokines in TBEV-mediated neurological disease are poorly understood.MethodsBALB/c mice were intracerebrally injected with TBEV, followed by evaluation of chemokine and cytokine profiles using protein array analysis. The virus-infected mice were treated with the CC chemokine antagonist Met-RANTES or anti-RANTES mAb to determine the role of RANTES in affecting TBEV-induced neurological disease. The underlying signaling mechanisms were delineated using RANTES promoter luciferase reporter assay, siRNA-mediated knockdown, and pharmacological inhibitors in human brain-derived cell culture models.ResultsIn a mouse model, pathological features including marked inflammatory cell infiltrates were observed in brain sections, which correlated with a robust up-regulation of RANTES within the brain but not in peripheral tissues and sera. Antagonizing RANTES within CNS extended the survival of mice and reduced accumulation of infiltrating cells in the brain after TBEV infection. Through in vitro studies, we show that virus infection up-regulated RANTES production at both mRNA and protein levels in human brain-derived cell lines and primary progenitor-derived astrocytes. Furthermore, IRF-3 pathway appeared to be essential for TBEV-induced RANTES production. Site mutation of an IRF-3-binding motif abrogated the RANTES promoter activity in virus-infected brain cells. Moreover, IRF-3 was activated upon TBEV infection as evidenced by phosphorylation of TBK1 and IRF-3, while blockade of IRF-3 activation drastically reduced virus-induced RANTES expression.ConclusionsOur findings together provide insights into the molecular mechanism underlying RANTES production induced by TBEV, highlighting its potential importance in the process of neuroinflammatory responses to TBEV infection.
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DOI：
10.1084/jem.20070608
发表时间：
2008-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Di Liberto D;Locati M;Caccamo N;Vecchi A;Meraviglia S;Salerno A;Sireci G;Nebuloni M;Caceres N;Cardona PJ;Dieli F;Mantovani A
通讯作者：
Mantovani A
影响因子：
5.4
作者：
Errett, John S.;Suthar, Mehul S.;Gale, Michael, Jr.
通讯作者：
Gale, Michael, Jr.
影响因子：
12
作者：
Doerrbecker, Bastian;Dobler, Gerhard;Hufert, Frank T.
通讯作者：
Hufert, Frank T.
影响因子：
5.4
作者：
Chen, CJ;Chen, JH;Raung, SL
通讯作者：
Raung, SL
影响因子：
16.8
作者：
Appay, V;Rowland-Jones, SL
通讯作者：
Rowland-Jones, SL