Complexity of the microglial activation pathways that drive innate host responses during lethal alphavirus encephalitis in mice.
Complexity of the microglial activation pathways that drive innate host responses during lethal alphavirus encephalitis in mice.
复制标题
小鼠致命甲病毒脑炎期间驱动先天宿主反应的小胶质细胞激活途径的复杂性。
DOI：
10.1042/an20120016
复制
发表时间：
2012
期刊：
影响因子：
4.7
通讯作者：
Irani,DavidN
中科院分区：
文献类型：
--
作者：
Esen,Nilufer;Blakely,PennelopeK;Rainey-Barger,EmilyK;Irani,DavidN
小胶质细胞表达多种tlr （toll样受体），并提供重要的宿主防御入侵中枢神经系统的病毒。尽管先前的研究表明，这些细胞在小鼠实验性甲型病毒性脑炎期间被激活，产生影响病毒复制、组织炎症和神经元存活的细胞因子和趋化因子，但在这种情况下控制小胶质细胞激活的特定PRRs（模式识别受体）和信号传导中间体仍不清楚。为了在体内直接研究这些问题，消融了特定TLR信号分子的小鼠被NSV（神经适应性Sindbis病毒）和CNS病毒滴度刺激，炎症反应和临床结果随时间推移而变化。为了在小胶质细胞中解决这一问题，我们在体外研究了非NSV对野生型和突变动物大脑原代细胞的影响。从病毒的角度来看，激活小胶质细胞需要剥去病毒外壳和完整的病毒基因组；灭活病毒颗粒没有引起可测量的小胶质细胞反应。在靶细胞水平上，NSV触发小胶质细胞中的多个PRRs，通过不重叠的信号通路产生广泛的炎症介质。在体内，令人惊讶的是，疾病存活与tlr驱动的反应无关，但仍然需要i型干扰素（IFN）的产生来控制中枢神经系统病毒的复制。有趣的是，内质网蛋白UNC93b1促进了宿主的存活，而不依赖于其对内体TLR信号的已知影响。综上所述，这些数据表明，甲病毒通过多个PRRs激活小胶质细胞，突出了这些感染引发中枢神经系统宿主反应的信号网络的复杂性。
Microglia express multiple TLRs (Toll-like receptors) and provide important host defence against viruses that invade the CNS (central nervous system). Although prior studies show these cells become activated during experimental alphavirus encephalitis in mice to generate cytokines and chemokines that influence virus replication, tissue inflammation and neuronal survival, the specific PRRs (pattern recognition receptors) and signalling intermediates controlling microglial activation in this setting remain unknown. To investigate these questions directlyin vivo, mice ablated of specific TLR signalling molecules were challenged with NSV (neuroadapted Sindbis virus) and CNS viral titres, inflammatory responses and clinical outcomes followed over time. To approach this problem specifically in microglia, the effects of NSV on primary cells derived from the brains of wild-type and mutant animals were characterizedin vitro.From the standpoint of the virus, microglial activation required viral uncoating and an intact viral genome; inactivated virus particles did not elicit measurable microglial responses. At the level of the target cell, NSV triggered multiple PRRs in microglia to produce a broad range of inflammatory mediators via non-overlapping signalling pathways.In vivo, disease survival was surprisingly independent of TLR-driven responses, but still required production of type-I IFN (interferon) to control CNS virus replication. Interestingly, the ER (endoplasmic reticulum) protein UNC93b1 facilitated host survival independent of its known effects on endosomal TLR signalling. Taken together, these data show that alphaviruses activate microglia via multiple PRRs, highlighting the complexity of the signalling networks by which CNS host responses are elicited by these infections.