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（COVS）是人和动物中广泛的RNA病毒。小鼠COV，小鼠肝炎病毒（MHV）是II组COV的原型。不同的MHV分离株诱导与急性和慢性脱髓鞘相关的急性致命性脑炎和脑脊髓炎。在没有明显的传染病毒的情况下，慢性病理变化与可疑或潜在病毒病因（例如多发性硬化症）的人中枢神经系统疾病相似。在急性感染期间，神经元和神经胶质细胞都变得有效地感染。哺乳动物Toll样受体（TLR）构成了一个模式识别受体家族，可检测与病原体相关的分子模式。病毒可能通过多种TLR触发炎症性细胞因子产生。关于病毒感染的TLR的相互作用和亚细胞定位知之甚少，以及TLR的病毒感知如何影响脑炎预后。 COV感染是否通过TLR激活炎症反应，如果是，则主要用于先天反应的TLR仍然未知。在这里，我们将检验以下假设：COV可以通过调节TLR响应来抵消中枢神经系统中的先天免疫反应。使用两种MHV菌株在神经损伤方面显着差异（MHV-JHM，一种高度神经性肺部的菌株，会产生严重且通常是致命性脑炎；以及MHV-A59，一种轻度神经性呼吸的菌株，一种急性脑膜炎和慢性疾病的急性脑膜疾病，我们的表达方式，我们的表达方式有所不同） 3，以及TLR2和3的功能后果（NF-？B激活，细胞因子产生）。因此，我们的具体目的是：1）定义TLR介导的炎症反应的COV决定因素，并具有一组明确定义的重组野生型野生型和偶然的病毒率； 2）确定TLR2和TLR3在野生型和基因敲除小鼠中通过发病机理研究在冠状病毒诱导的脑炎脑炎中的作用，以及在原发性小胶质细胞和星形胶质细胞培养物中的细胞因子和趋化因子的产生。该实验模型将提供一个独特的机会来定义TLR2和TLR3-介导的神经炎症反应的作用，并更好地理解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：TLRS途径在病毒识别与病毒发病机理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，并更好地理解TLR在病毒脑炎和慢性脱髓鞘中的作用。