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Role of RIG-like receptors in virally induced CNS inflammation

RIG样受体在病毒诱导的中枢神经系统炎症中的作用

基本信息

批准号：
8021833
负责人：
Valery Zurabovich Grdzelishvili
金额：
$ 6.83万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
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/8021833
关键词：
Animals Astrocytes Binding Borna disease virus Boxing Brain Cells Central Nervous System Diseases Central Nervous System Infections Central Nervous System Viral Diseases Development Encephalitis Endothelial Cells Event Exhibits Exposure to Family Filoviridae Funding Future Generations Genes Goals Human Immune response Immunity In Vitro Infection Inflammation Inflammation Mediators Inflammatory Intranasal Administration Invaded Investigation Laboratories Leukocytes Maintenance Mediating Microglia Modeling Mononegavirales Morbidity - disease rate Mus Nerve Degeneration Nervous System Trauma Neuraxis Neuroglia Neurons Neurotropism Newcastle disease virus Olfactory Receptor Neurons Organ Paralysed Paramyxovirus Pattern recognition receptor Pilot Projects Play Positioning Attribute Production RNA Helicase RNA Viruses Rabies Rabies virus Regulation Relative (related person)Research Project Grants Rhabdoviridae Role Solid T-Lymphocyte Testing Trauma Tretinoin Vesicular stomatitis Indiana virus Viral Viral Antigens Viral Load result Virus Virus Diseases Work brain cell cell type cytokine helicase in vivo in vivo Model member mortality nervous system disorder neurotropic neurotropic virus novel olfactory bulb pathogen public health relevance receptor receptor expression research study response

项目摘要

DESCRIPTION (provided by applicant): While glial cells are recognized for their roles in maintaining neuronal function, there is growing appreciation of the ability of resident brain cells to initiate and/or regulate inflammation following trauma or infection in the central nervous system (CNS). Astrocytes and microglia are uniquely positioned to detect and respond to invading pathogens of the CNS and previous studies have demonstrated the ability of these cells to produce key inflammatory mediators following exposure to members of the Mononegavirales order of viruses that are the causative agents of lethal human CNS diseases, notably rabies. However, the mechanisms by which resident cells of the CNS perceive such viral challenges have not been defined. Recently, several cytosolic DExD/H box RNA helicases have been described that can bind early viral replicative intermediates leading to the realization that retinoic acid-inducible gene I (RIG-I)-like helicases, function as intracellular receptors for RNA viruses. We have recently completed investigations showing that astrocytes and microglia can be infected with, and respond to, a model neurotropic rhabdovirus, vesicular stomatitis virus (VSV). Importantly, we have also completed a characterization of RIG-I-like receptor (RLR) expression in these resident glial cell types. In the experiments described in this R03 pilot study, we will assess the role of RLR proteins in the initiation and/or maintenance of inflammatory immune responses of glia to a model neurotropic rhabdovirus. We will employ isolated cultures of astrocytes and microglia derived from normal animals and mice genetically deficient in the expression of RLR to assess the relative importance of these novel receptors in cytokine production following in vitro exposure to VSV. Furthermore, we will administer VSV intranasally in wild type and RLR deficient mice animals and assess subsequent viral burden and inflammatory CNS damage following infection to determine the relative importance of RIG-I in the progression of infection and/or CNS inflammatory damage in an in vivo setting. Results from these studies are anticipated to reveal that this RLR molecule represents an important mechanism underlying the initiation and/or maintenance of immune responses during a model neurotropic viral infection and will contribute significantly to our understanding of the events that underlie the development of either protective host responses within the brain or the progression of damaging CNS inflammation. Importantly, these initial studies will provide a solid rationale for more comprehensive investigations into the regulation and role of this novel viral pattern recognition receptor during CNS infection for which future R01 mechanism funding will be sought. PUBLIC HEALTH RELEVANCE: Members of the Mononegavirales order of viruses are the causative agents of lethal human central nervous system diseases, notably rabies. However, the mechanisms by which resident brain cells recognize such viral challenges have not been defined. In the proposed studies, we will we will assess the role of retinoic acid-inducible gene I (RIG-I) in the progression of damaging brain inflammation following infection with a model neurotropic rhabdovirus.

描述（由申请人提供）：虽然胶质细胞在维持神经元功能方面的作用已被公认，但人们越来越认识到常驻脑细胞在中枢神经系统（CNS）创伤或感染后引发和/或调节炎症的能力。星形胶质细胞和小胶质细胞具有独特的定位，可以检测和响应CNS的入侵病原体，并且先前的研究已经证明了这些细胞在暴露于作为致命的人类CNS疾病（特别是狂犬病）的病原体的单负病毒目病毒的成员后产生关键炎症介质的能力。然而，CNS的驻留细胞感知这种病毒挑战的机制尚未确定。最近，已经描述了几种胞质DExD/H盒RNA解旋酶，它们可以结合早期病毒复制中间体，从而认识到视黄酸诱导基因I（RIG-I）样解旋酶的功能是RNA病毒的细胞内受体。我们最近完成的调查表明，星形胶质细胞和小胶质细胞可以感染，并响应，模型嗜神经弹状病毒，水泡性口炎病毒（VSV）。重要的是，我们还完成了RIG-I样受体（RLR）在这些居民神经胶质细胞类型的表达的表征。在R 03初步研究中描述的实验中，我们将评估RLR蛋白在启动和/或维持胶质细胞对模型嗜神经弹状病毒的炎症免疫应答中的作用。我们将采用分离培养的星形胶质细胞和小胶质细胞来源于正常动物和小鼠遗传缺陷的RLR表达，以评估这些新的受体在体外暴露于VSV后的细胞因子产生的相对重要性。此外，我们将在野生型和RLR缺陷型小鼠动物中鼻内施用VSV，并评估感染后的后续病毒负荷和炎性CNS损伤，以确定RIG-I在体内环境中感染和/或CNS炎性损伤进展中的相对重要性。这些研究的结果预计将揭示，这种RLR分子代表了模型嗜神经病毒感染期间免疫应答启动和/或维持的重要机制，并将显著有助于我们理解脑内保护性宿主应答或损害性CNS炎症进展的基础事件。重要的是，这些初步研究将为更全面地研究CNS感染期间这种新型病毒模式识别受体的调控和作用提供坚实的理论基础，未来将寻求R 01机制的资助。公共卫生关系：单负性病毒目病毒的成员是致命的人类中枢神经系统疾病，特别是狂犬病的病原体。然而，常驻脑细胞识别这种病毒挑战的机制尚未确定。在拟议的研究中，我们将评估视黄酸诱导基因I（RIG-I）在模型嗜神经弹状病毒感染后损害性脑炎症进展中的作用。