Encephalitic viral infection and susceptibility to dopaminergic neurotoxins

项目摘要 这个虚拟联盟项目的总体重点是神经炎症和神经免疫轴， 病毒感染与环境神经毒素损伤易感性之间的关键联系。神经炎症 神经胶质细胞的活化可能代表神经疾病的“两次打击”理论中的重要因果联系， 使易受影响的大脑区域对来自不同环境应激源的损伤敏感，从而促进 临床疾病的发作。拟议的虚拟联盟将研究如何感染常见的 遇到RNA病毒，包括西方马脑炎病毒（WEEV）和H1N1流感病毒， 当前全球流行的流感病毒，影响暴露于以下神经系统结果的严重性： 神经毒性金属和杀虫剂。在动物模型中检查的神经炎症机制将进行比较 对职业性暴露于锰（Mn）的个体进行神经炎症的高级PET成像， 结合他们的病毒暴露史分析。这个虚拟联盟将检查信令 小胶质细胞和星形胶质细胞在病毒暴露后调节神经炎性损伤的机制 和选定的环境神经毒素使用转基因小鼠模型以及临床成像在锰- 暴露的病人。该联盟将汇集神经病毒学和神经变性方面的合作者 （理查德·斯迈恩，托马斯杰斐逊大学）、神经病学和临床影像学（布拉德·拉塞特，华盛顿 圣路易斯大学）和神经炎症（罗纳德Tjalkens，科罗拉多州立大学），以确定关键 调节对感染性和神经毒性环境暴露反应的神经炎症机制 会增加患神经退行性疾病的风险我们的核心假设是， 脑炎病毒感染引起小胶质细胞和星形胶质细胞的持续性炎症表型， 神经毒性损伤的易感性。这一假设将通过以下相互关联的具体目标进行检验： 具体目标1（Tjalkens，科罗拉多州立大学）-确定小胶质细胞中的炎症信号通路 由西方马脑炎病毒（WEEV）调节，促进神经胶质细胞活化和神经元损伤， 锰和鱼藤酮;具体目标2（Smeyne，托马斯杰斐逊大学）-确定机制， 其中H1N1流感病毒改变锰和鱼藤酮对神经元损伤的作用;特异性目的3 （Racette，华盛顿大学医学院）-描述神经功能障碍的模式， 锰（Mn）暴露工人的小胶质细胞活化。我们预计，这个虚拟联盟将有一个 对我们理解环境神经毒素和病毒之间的相互作用产生了重大影响， 促进神经系统疾病，这是目前还知之甚少。这种相互作用很可能 鉴于病毒感染和暴露于 神经毒剂在一般人群中。拟议的ViCTER联盟通过以下方式解决了这一问题： 跨学科方法将强大的基础研究模型与先进的PET神经成像相结合， 职业性暴露于Mn的患者人群，将检查其病毒感染史。的 这些研究的结果很可能为更好的识别和 预防神经退行性疾病的环境风险因素。

Project Summary The overall focus of this Virtual Consortium project is on neuroinflammation and the neuro-immune axis as a critical link between viral infection and susceptibility to injury from environmental neurotoxins. Neuroinflammatory activation of glial cells may represent an important causal link in the `two-hit' theory of neurological disease, sensitizing susceptible brain regions to damage from distinct environmental stressors and thereby promoting the onset of clinical disease. The proposed Virtual Consortium will examine how infection with commonly encountered RNA viruses, including Western Equine Encephalitis virus (WEEV) and H1N1 influenza virus, the current worldwide pandemic flu virus, influences the severity of neurological outcomes following exposure to neurotoxic metals and pesticides. Neuroinflammatory mechanisms examined in animal models will be compared to advanced PET imaging of neuroinflammation in individuals occupationally exposed to manganese (Mn) in conjunction with an analysis of their history of viral exposure. This Virtual Consortium will examine signaling mechanisms in microglia and astrocytes that regulate neuroinflammatory injury following exposure to viruses and selected environmental neurotoxins using both transgenic mouse models as well as clinical imaging in Mn- exposed patients. The Consortium will bring together collaborators in neurovirology and neurodegeneration (Richard Smeyne, Thomas Jefferson University), neurology and clinical imaging (Brad Racette, Washington University, St. Louis) and neuroinflammation (Ronald Tjalkens, Colorado State University) to identify key neuroinflammatory mechanisms modulating the response to infectious and neurotoxic environmental exposures that could increase the risk of developing neurodegenerative disease. It is our central hypothesis that encephalitic viral infection causes a persistent inflammatory phenotype in microglia and astrocytes that enhances susceptibility to neurotoxic injury. This hypothesis will be tested by the following interconnected Specific Aims: Specific Aim 1 (Tjalkens, Colorado State University) - Identify inflammatory signaling pathways in microglia modulated by Western Equine Encephalitis Virus (WEEV) that promote glial activation and neuronal injury from manganese and rotenone; Specific Aim 2 (Smeyne, Thomas Jefferson University) - Determine mechanisms by which H1N1 influenza virus alters the effects of manganese and rotenone on neuronal injury; Specific Aim 3 (Racette, Washington University School of Medicine) - Characterize patterns of neurological dysfunction and microglial activation in manganese (Mn) exposed workers. We expect that this Virtual Consortium will have a significant impact on our understanding of interactions between environmental neurotoxins and viruses that can promote neurological disease, which are currently only poorly understood. Such interactions are likely to have enormous implications to public health, given the widespread incidence of both viral infections and exposure to neurotoxic agents in the general population. The proposed ViCTER consortium addresses this problem with an interdisciplinary approach integrating powerful basic research models with advanced PET neuroimaging in a patient population occupationally exposed to Mn that will be examined for a history of viral infections. The outcomes from these studies are very likely to inform better policy decisions regarding identification and prevention of environmental risk factors for neurodegenerative disease.