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: 8598010
• 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/8598010
• 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）： 病毒通过杀死大脑和脊髓内神经元的基本功能来诱导中枢神经系统（CNS）。我们建议使用良好特征的病毒诱导的中枢神经系统疾病模型来研究病毒导致神经元细胞死亡以及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涉及的特定细胞信号通路，并评估这些信号通路作为病毒诱导的中枢神经系统疾病的治疗靶标。预计我们的实验将导致鉴定出病毒诱导的中枢神经系统疾病的新型治疗靶标。 凋亡是病毒脑炎期间病毒诱导的细胞死亡的确定机制，并在大脑中发生了多种病毒的实验感染。凋亡还成为病毒诱导的人类脊髓炎的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execution子手caspase导致病毒诱导的脑炎的严重程度降低。在特定目标1中，我们将测试以下假设：抑制导致凋亡细胞死亡的信号传导途径会预防神经元死亡，并为病毒引起的脑和脊髓疾病提供新的靶标感染了多种临床相关病毒。新生儿小鼠的葡萄病毒感染提供了一个良好的模型系统，用于理解大脑和脊髓内的病毒发病机理。我们已经确定，在异病毒感染后，在大脑中激活了外在和内在的凋亡途径和JNK信号传导，并有助于依默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）在我们最近开发的葡萄病毒诱导的脊髓炎的模型中：（ii） 在感染了西尼罗河病毒（WNV）和单纯疱疹病毒（HSV）的小鼠的大脑中：（iii）病毒（依维病毒，WNV，HSV）感染了体内脑切片培养和：（iv）在人体组织中患有病毒诱导的CNS病患者的人体组织中的病毒感染，并在病毒诱导的患者中表现出病毒性的作用。 中枢神经系统的病毒感染导致先天免疫反应激活，包括干扰素（IFN）的上调和IFN刺激基因（ISG）的表达增加。 ISG影响凋亡，尽管发生这种情况的机制，并且这些基因在病毒发病机理中的作用仍然未知。在特定的目标2中，我们将研究特定ISG，具有推定的凋亡功能的作用，在病毒（eovirus，wnv，hsv）中，在病毒感染过体内脑切片培养和病毒诱导的CNS病患者的组织中，在小鼠脑和脊髓内引起的发病机理。 神经胶质性（小胶质细胞和星形胶质细胞的激活）是神经炎症的标志。在病毒性脑炎期间，在大脑中发现了与日本脑炎病毒（JEV）感染后的体外和体内胶质性和体内的炎症介质。然而，神经胶质病在急性病毒诱导的中枢神经系统疾病中的作用尚不完全了解，尤其是在脊髓中。尽管神经胶质细胞增生可能通过促进被感染细胞的去除来抑制婚姻复制的作用，但已提出这种保护性 从激活的神经胶质中释放几个因素，这些因素诱导神经变性和严重损伤对旁观者细胞的释放可能会掩盖角色。在特定目标3中，我们假设神经胶质病在CNS病毒感染后有助于发病机理。我们将通过研究病毒脑切片的病毒感染后，通过研究病毒（埃他肠疾病病毒，WNV，HSV）在小鼠脑和脊髓内的发病机理的作用来检验该假设。