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

• 批准号: 7897067
• 负责人: SONIA NAVAS-MARTIN
• 金额: $ 7.69万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 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/7897067
• 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; RNA Viruses; 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

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）是广泛存在于人类和动物中的新兴RNA病毒。鼠型冠状病毒，即小鼠肝炎病毒（MHV），是II类冠状病毒的原型。不同的MHV分离株可诱发急性致死性脑炎和脑脊髓炎，并伴有急性和慢性脱髓鞘。在没有明显感染性病毒的情况下，慢性病理变化与怀疑或潜在病毒病因的人类中枢神经系统疾病相似，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感染。哺乳动物toll样受体（Toll-Like Receptors, TLRs）是一类模式识别受体，用于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tlr在中枢神经系统中对病毒感染的相互作用和亚细胞定位，以及tlr对病毒的感知如何影响脑炎的预后，我们知之甚少。冠状病毒感染是否通过TLR激活炎症反应，如果是，哪些TLR主要用于先天反应仍然未知。在这里，我们将验证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。使用两种神经毒力明显不同的MHV毒株（MHV- jhm，一种高度神经毒力毒株，可产生严重且通常致命的脑炎；MHV- a59，一种轻度神经毒力毒株，可诱发急性脑膜脑炎和慢性脱髓鞘），我们有初步数据显示它们在TLR2和3的表达调节以及功能后果(NF-？B活化，细胞因子产生)的mhv感应TLR2和3。因此，我们的具体目标是：1)用一组定义明确的重组野生型和嵌合病毒确定tlr介导的炎症反应的冠状病毒决定因素；2)在体内研究TLR2和TLR3在冠状病毒诱导的脑炎中的作用，研究野生型和敲除小鼠的发病机制，并在体外研究原代小胶质细胞和星形胶质细胞培养中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，并更好地了解TLR2和TLR3在病毒性脑炎和慢性脱髓鞘中的功能。