Mechanisms of virus-induced injury in the brain and spinal cord

病毒引起的脑和脊髓损伤的机制

• 批准号: 8413416
• 负责人: Kenneth L. Tyler
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413416
• 关键词: Acute; Affect; Alzheimer' s Disease; Animal Model; Antiviral Agents; Apoptosis; Apoptotic; Astrocytes; Basic Science; Biological Models; Brain; Caspase; Cell Death; Cells; Central Nervous System Diseases; Central Nervous System Viral Diseases; Cessation of life; Disease; Encephalitis; Excision; Future; Genes; Gliosis; Grant; Health; Human; Immune response; In Vitro; Infection; Inflammation Mediators; Injury; Interferons; JUN gene; Japanese encephalitis virus; Lead; Microglia; Modeling; Morbidity - disease rate; Motor Neurons; Mus; Myelitis; Neonatal; Nerve Degeneration; Neuraxis; Neuroglia; Neuronal Injury; Neurons; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Play; Population; Prevention; Public Health; Reoviridae Infections; Reovirus; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Simplexvirus; Slice; Spinal Cord; Spinal Cord Diseases; Staging; Testing; Tissues; Treatment Efficacy; Up-Regulation; Veterans; Viral; Viral Encephalitis; Viral Pathogenesis; Virus; Virus Diseases; West Nile virus; caspase-3; cell injury; cellular targeting; clinically relevant; design; fibroblast growth factor 9; human BIRC4 protein; human tissue; in vivo; killings; mortality; mouse model; nervous system disorder; neuroinflammation; neuron apoptosis; neuron loss; neurotoxic; new therapeutic target; novel; novel therapeutics; pathogen; prevent; research study; spinal cord and brain injury; therapeutic target; transcription factor PML; translational study

DESCRIPTION (provided by applicant): Viruses induce disease in the central nervous system (CNS) by either killing or disrupting essential functions of neurons within the brain and spinal cord. We propose to use well characterized models of virus-induced CNS disease to investigate the mechanisms by which viruses cause neuronal cell death and injury to the brain and spinal cord. We will delineate the specific cell signaling pathways involved in virus-induced death and tissue injury within the CNS and evaluate these signaling pathways as therapeutic targets for virus-induced CNS disease. Our experiments are expected to lead to the identification of novel therapeutic targets for virus- induced CNS disease. Apoptosis is an established mechanism of virus-induced cell death during viral encephalitis and occurs in the brain following experimental infection with a wide variety of viruses. Apoptosis is also emerging as a mechanism of motor neuron cell death in virus-induced myelitis in humans. Inhibition of caspase 3, the executioner caspase of apoptotic cell death, results in decreased severity of virus-induced encephalitis. In specific aim 1 we will test the hypothesis that inhibition of the signaling pathways that lead to apoptotic cell death wil prevent neuronal death and provide novel targets for virus induced brain and spinal cord disease following infection with a variety of clinically relevant viruses. Reovirus infection of neonatal mice provides a well characterized model system for understanding viral pathogenesis within both the brain and spinal cord. We have already identified that the extrinsic and intrinsic apoptotic pathways and JNK signaling are activated in the brain following reovirus infection and contribute to reovirus-induced neuronal apoptosis. We propose to identify whether these pathways are also activated: (i) in our recently developed model of reovirus-induced myelitis: (ii) in the brains of mice infected with West Nile Virus (WNV) and herpes simplex virus (HSV): (iii) following virus (reovirus, WNV, HSV) infection of ex vivo brain slice cultures and: (iv) in human tissue from patients with virus-induced CNS disease, and to characterize their role in viral pathogenesis. Virus infection of the CNS results in activation of innate immune responses, including the up-regulation of interferon (IFN) and increased expression of IFN stimulated genes (ISG). ISG influence apoptosis, although the mechanism by which this occurs and the role of these genes in viral pathogenesis remains unknown. In specific aim 2 we will investigate the role of specific ISG, with putative apoptotic functions, in virus (reovirus, WNV, HSV)-induced pathogenesis within the mouse brain and spinal cord, following viral infection of ex vivo brain slice cultures and in tissue from patients with virus-induced CNS disease. Gliosis (activation of microglia and astrocytes) is a hallmark of neuroinflammation. Gliosis has been demonstrated in vitro and in vivo following infection with Japanese encephalitis virus (JEV) and inflammatory mediators associated with gliosis have been detected in the brain during viral encephalitis. However, the role of gliosis in acute virus-induced CNS disease remains incompletely understood, particularly within the spinal cord. Although gliosis may play a role in inhibiting virl replication by facilitating the removal of infected cells it has been proposed that this protective role may be overshadowed by the release of several factors from activated glia that induce neurodegeneration and severe injury to bystander cells. In specific aim 3 we hypothesize that gliosis contributes to pathogenesis following viral infections of the CNS. We will test this hypothesis by investigating the role gliosis in virus (reovirus, WNV, HSV)-induced pathogenesis within the mouse brain and spinal cord, following viral infection of ex vivo brain slice cultures and in tissue from patients with virus-induced CNS disease.

描述（由申请人提供）： 病毒通过杀死或破坏大脑和脊髓内神经元的基本功能来诱发中枢神经系统（CNS）疾病。我们建议使用病毒引起的中枢神经系统疾病的良好特征模型来研究病毒导致神经元细胞死亡以及大脑和脊髓损伤的机制。我们将描述中枢神经系统内病毒诱导的死亡和组织损伤所涉及的特定细胞信号传导途径，并评估这些信号传导途径作为病毒诱导的中枢神经系统疾病的治疗靶点。我们的实验有望确定病毒引起的中枢神经系统疾病的新治疗靶点。 细胞凋亡是病毒性脑炎期间病毒诱导细胞死亡的既定机制，在实验性感染多种病毒后发生在大脑中。细胞凋亡也正在成为人类病毒引起的脊髓炎运动神经元细胞死亡的一种机制。抑制 caspase 3（凋亡细胞死亡的执行者 caspase）可降低病毒诱发的脑炎的严重程度。在具体目标 1 中，我们将测试以下假设：抑制导致细胞凋亡的信号通路将防止神经元死亡，并为感染各种临床相关病毒后病毒诱发的脑和脊髓疾病提供新的靶点。新生小鼠的呼肠孤病毒感染提供了一个特征明确的模型系统，用于了解大脑和脊髓内的病毒发病机制。我们已经确定，呼肠孤病毒感染后，大脑中的外在和内在凋亡途径以及 JNK 信号传导被激活，并导致呼肠孤病毒诱导的神经元凋亡。我们建议确定这些途径是否也被激活：（i）在我们最近开发的呼肠孤病毒诱导的脊髓炎模型中：（ii） 感染西尼罗病毒 (WNV) 和单纯疱疹病毒 (HSV) 的小鼠大脑中：(iii) 离体脑切片培养物感染病毒（呼肠孤病毒、WNV、HSV）后，以及：(iv) 患者的人体组织中与病毒引起的中枢神经系统疾病相关，并表征它们在病毒发病机制中的作用。 中枢神经系统的病毒感染会导致先天免疫反应的激活，包括干扰素 (IFN) 的上调和 IFN 刺激基因 (ISG) 表达的增加。 ISG 影响细胞凋亡，尽管其发生机制以及这些基因在病毒发病机制中的作用仍不清楚。在具体目标 2 中，我们将研究体外脑切片培养物和组织中的病毒感染后，具有推定的细胞凋亡功能的特定 ISG 在病毒（呼肠孤病毒、WNV、HSV）诱导的小鼠大脑和脊髓内发病机制中的作用来自患有病毒引起的中枢神经系统疾病的患者。 胶质增生（小胶质细胞和星形胶质细胞的激活）是神经炎症的标志。感染日本脑炎病毒（JEV）后，体外和体内均已证实存在神经胶质增生，并且在病毒性脑炎期间在大脑中检测到与神经胶质增生相关的炎症介质。然而，神经胶质增生在急性病毒引起的中枢神经系统疾病中的作用仍不完全清楚，特别是在脊髓内。尽管神经胶质增生可能通过促进感染细胞的去除而在抑制病毒复制中发挥作用，但有人提出这种保护性作用 激活的神经胶质细胞释放的多种因子可能会掩盖其作用，这些因子会导致神经变性和旁观者细胞的严重损伤。在具体目标 3 中，我们假设神经胶质增生有助于中枢神经系统病毒感染后的发病机制。我们将通过研究病毒感染离体脑切片培养物和病毒引起的中枢神经系统疾病患者的组织后，神经胶质增生在小鼠大脑和脊髓内病毒（呼肠孤病毒、WNV、HSV）诱导的发病机制中的作用来检验这一假设。 。