Role of toll-like receptors 2 and 3 in coronavirus-induced encephalitis

Toll样受体2和3在冠状病毒引起的脑炎中的作用

基本信息

批准号：
8024522
负责人：
SONIA NAVAS-MARTIN
金额：
$ 7.55万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8024522
关键词：
Acute Acute Disease Address Affect Age Animals Astrocytes Brain Categories Cell Line Cells Central Nervous System Diseases Chronic Coronavirus Coronavirus Infections Cytokine Activation Data Disease Dose Double-Stranded RNA Effector Cell Employee Strikes Encephalitis Encephalomyelitis Etiology Experimental Models Family Figs - dietary Human Immune Immune response Immunity In Vitro Infection Inflammatory Inflammatory Response Interleukin-6 Knock-out Knockout Mice Lead Maps Mediating Mediator of activation protein Meningoencephalitis Microglia Modeling Molecular Multiple Sclerosis Murine hepatitis virus Mus National Institute of Allergy and Infectious Disease Neuroglia Neurons Organ Outcome Pathogenesis Pathology Pathway interactions Pattern Pattern recognition receptor Predisposition Production RNA Viruses Receptor Activation Recombinants Relative (related person)Reporting Role Route Severe Acute Respiratory Syndrome Severities Signal Transduction Spinal Cord Sterility System TLR2 gene TLR3 gene Testing Toll-Like Receptor 2 Toll-Like Receptor Pathway Toll-like receptors Transcriptional Activation Transducers Viral Viral Antigens Viral Encephalitis Viral Pathogenesis Viral Proteins Virus Virus Diseases Wild Type Mouse base chemokine chronic demyelination cytokine in vitro Model in vivo macrophage man neurovirulence pathogen positional cloning prototype public health relevance recombinant virus response viral RNA

项目摘要

DESCRIPTION (provided by applicant): Coronaviruses (CoVs) are widespread emerging RNA viruses in man and animals. Murine CoV, mouse hepatitis virus (MHV), is the prototype of group II CoV. Different MHV isolates induce acute fatal encephalitis and encephalomyelitis associated with acute and chronic demyelination. The chronic pathological changes in the absence of overt infectious virus are similar to human CNS diseases with suspected or potential viral etiologies, such as multiple sclerosis. During acute infection, both neurons and glial cells become productively infected. Mammalian Toll-Like Receptors (TLRs) constitute a family of pattern recognition receptors which detect conserved pathogen-associated molecular patterns. Viruses may trigger inflammatory cytokine production via multiple TLRs. Little is known about the interplay and subcellular localization of TLRs in the CNS in response to viral infections, and how virus sensing by TLRs may affect encephalitis outcome. Whether CoV infection activates inflammatory responses via TLRs and if so, which TLR is primarily utilized for the innate response remains unknown. Here, we will test the hypothesis that CoVs may counteract the innate immune response in the CNS by modulation of TLR responses. Using two MHV strains that markedly differ in their neurovirulence (MHV-JHM, a highly neurovirulent strain that produces severe and often fatal encephalitis; and MHV-A59, a mildly neurovirulent strain that induces acute meningoencephalitis and chronic demyelination), we have preliminary data demonstrating striking differences between them in the modulation of expression of TLR2 and 3, and in the functional consequences (NF-?B activation, cytokine production) of MHV-sensing by TLR2 and 3. Therefore, our Specific Aims are: 1) to define CoV determinants of TLR-mediated inflammatory response with a well-defined set of recombinant wild-type and chimeric viruses; and 2) to determine the role of TLR2 and TLR3 in coronavirus-induced encephalitis in vivo with pathogenesis studies in wild-type and knockout mice, and ex vivo investigating cytokine and chemokine production in primary microglia and astrocyte cultures. This experimental model will provide a distinctive opportunity to define the role of TLR2- and TLR3- mediated neuroinflammatory response and a better understanding of the function of TLR2 and TLR3 in viral encephalitis and chronic demyelination. PUBLIC HEALTH RELEVANCE: The relative contribution of TLRs pathways in viral recognition versus viral pathogenesis is unclear. This experimental model will provide a distinctive opportunity to define coronavirus determinants of TLR2 and 3- mediated inflammatory response and a better understanding of the role of TLRs in viral encephalitis and chronic demyelination.

描述（由申请人提供）：冠状病毒 (CoV) 是人类和动物中广泛传播的新兴 RNA 病毒。鼠科病毒，即小鼠肝炎病毒（MHV），是 II 族冠状病毒的原型。不同的 MHV 分离株可诱发急性致命性脑炎和与急性和慢性脱髓鞘相关的脑脊髓炎。在没有明显传染性病毒的情况下的慢性病理变化类似于具有可疑或潜在病毒病因的人类中枢神经系统疾病，例如多发性硬化症。在急性感染期间，神经元和神经胶质细胞都被有效感染。哺乳动物 Toll 样受体 (TLR) 构成了一个模式识别受体家族，可检测保守的病原体相关分子模式。病毒可能通过多个 TLR 触发炎症细胞因子的产生。关于中枢神经系统中 TLR 响应病毒感染的相互作用和亚细胞定位，以及 TLR 感知病毒如何影响脑炎结果，人们知之甚少。冠状病毒感染是否通过 TLR 激活炎症反应，如果是的话，哪种 TLR 主要用于先天反应仍然未知。在这里，我们将检验冠状病毒可能通过调节 TLR 反应来抵消 CNS 中的先天免疫反应的假设。使用两种神经毒力显着不同的 MHV 毒株（MHV-JHM，一种高神经毒株，可引起严重且往往致命的脑炎；MHV-A59，一种轻度神经毒株，可诱发急性脑膜脑炎和慢性脱髓鞘），我们有初步数据证明它们之间在 TLR2 和 3 的表达调节以及功能后果（NF-κB 激活、细胞因子产生）方面存在显着差异。 TLR2 和 3 进行 MHV 感应。因此，我们的具体目标是：1）通过一组明确的重组野生型和嵌合病毒来定义 TLR 介导的炎症反应的 CoV 决定因素； 2) 通过野生型和基因敲除小鼠的发病机制研究，确定 TLR2 和 TLR3 在体内冠状病毒诱导的脑炎中的作用，并离体研究原代小胶质细胞和星形胶质细胞培养物中细胞因子和趋化因子的产生。该实验模型将为定义 TLR2 和 TLR3 介导的神经炎症反应的作用提供独特的机会，并更好地了解 TLR2 和 TLR3 在病毒性脑炎和慢性脱髓鞘中的功能。公共卫生相关性：TLR 通路在病毒识别与病毒发病机制中的相对贡献尚不清楚。该实验模型将为定义 TLR2 和 3 介导的炎症反应的冠状病毒决定因素提供独特的机会，并更好地了解 TLR 在病毒性脑炎和慢性脱髓鞘中的作用。