Role of Microglia in Protection Against West Nile Virus-induced CNS Injury: mechanisms and treatment strategies

小胶质细胞在预防西尼罗河病毒引起的中枢神经系统损伤中的作用：机制和治疗策略

• 批准号: 10513299
• 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 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513299
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Antigen-Presenting Cells; Arbovirus Encephalitis; Astrocytes; Basic Science; Bone Marrow Transplantation; Brain; Cells; Central Nervous System; Central Nervous System Diseases; Central Nervous System Infections; Cessation of life; Clinical; Cognitive; Data; Disease; Elderly; Excision; FDA approved; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Health; Hematopoietic Cell Growth Factors; Human; Immune; Immune system; Infection; Inflammatory; Injury; Invaded; Macrophage Colony-Stimulating Factor Receptor; Microglia; Modeling; Monitor; Morbidity - disease rate; Mus; Nerve Degeneration; Nervous System Trauma; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurons; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Peripheral Nervous System; Phagocytosis; Phagocytosis Inhibition; Play; Population; Probability; Proliferating; Recombinants; Recovery; Risk; Role; Severities; Slice; Spinal Cord; T cell response; T-Lymphocyte; Testing; Time; Tissues; Transplant Recipients; United States; Veterans; Viral; Viral Encephalitis; Virus; Virus Diseases; Virus Replication; West Nile viral infection; West Nile virus; White Blood Cell Count procedure; antagonist; antigen-specific T cells; cell injury; central nervous system injury; chemokine; comparison control; cytokine; efficacy evaluation; experimental study; improved; in vivo; leukemia; male; military veteran; mortality; nervous system disorder; neuroinflammation; neurotoxic; novel therapeutic intervention; pathogen; release factor; response; sargramostim; spinal cord and brain injury; therapeutic target; therapeutically effective; tissue injury; treatment strategy

Treatments for virus-induced diseases of the central nervous system (CNS) are sub-optimal or nonexistent. West Nile virus (WNV) is the most common cause of epidemic encephalitis within the US. This proposal will investigate the role of microglia during WNV infections of the CNS and will evaluate microglial stimulation as a potential treatment strategy for WNV-induced CNS disease. Virus infection of the CNS results in a robust host neuroinflammatory response, including the activation of CNS immune cells (microglia). The role of microglia in virus-induced CNS disease remains unclear. They likely play a protective role in facilitating the removal of infected cells and the recovery of damaged neurons. However, many of the factors released by microglia may contribute to injury within the CNS. Indeed, neuroinflammation in general and microglia activation in particular are key pathogenic components following neurologic injury and during noninfectious forms of neurologic and neurodegenerative disease. Our in vivo and ex vivo models will allow us to compare the role of microglia in the brain and spinal cord. Since microglia are central to a variety of CNS injury and disease pathologies, including neurodegenerative diseases, the proposed experiments will likely have wide reaching clinical implications. We have recently shown that depletion of microglia, with the colony stimulating factor receptor 1 (CSFR1) antagonist PLX5622, results in increased severity of WNV-induced CNS disease in mice that is associated with an increase in CNS viral titers. In Specific Aim 1 of this proposal we will use PLX5622 targeted depletion of microglia to determine whether microglia impact viral growth at the point of viral entry into the CNS, viral replication within the CNS, or viral clearance. Microglia function to identify and remove invading pathogens by phagocytosing infected or damaged cells, by acting as antigen presenting cells required to generate a complete antigen specific T cell response, and by secreting immune modulatory molecules. In Specific Aim 2 we will determine which of these mechanisms are required for microglia to inhibit WNV growth in the CNS. In Specific Aim 3 we will determine the efficacy of microglial stimulation as a treatment strategy for WNV-induced CNS disease. For these studies we will use granulocyte-macrophage colony-stimulating factor (GM-CSF), a haematopoietic growth factor and proinflammatory cytokine, that induces, proliferates, and activates microglia. Recombinant human GM-CSF is already FDA-approved to treat conditions in which white blood cell counts are low, such as in certain types of leukemia or bone marrow transplant recipients. GM-CSF and is currently being investigated as a potential treatment for cognitive problems related to Alzheimer's disease. Mice will be treated with recombinant human GM-CSF (Leukine) and will be monitored to determine viral CNS titers, virus-induced tissue injury and death, and the persistence of neurological sequelae in surviving mice.

中枢神经系统（CNS）病毒诱导疾病的治疗是次优或 不存在。西尼罗河病毒（WNV）是美国境内流行病的最常见原因。这 提案将研究小胶质细胞在中枢神经系统的WNV感染中的作用，并将评估小胶质细胞 刺激是WNV诱导的中枢神经系统疾病的潜在治疗策略。 中枢神经系统的病毒感染会导致强大的宿主神经炎症反应，包括 CNS免疫细胞（小胶质细胞）的激活。小胶质细胞在病毒引起的中枢神经系统疾病中的作用仍然存在 不清楚。他们可能在促进被感染细胞的去除和恢复方面发挥保护作用 受损的神经元。但是，小胶质细胞释放的许多因素可能导致在 CNS。实际上，神经炎症一般，特别是小胶质细胞激活是关键的致病性 神经系统损伤和神经退行性的非感染形式的成分 疾病。我们的体内和离体模型将使我们能够比较小胶质细胞在大脑和脊柱中的作用 绳索。由于小胶质细胞是各种中枢神经系统损伤和疾病病理的核心，包括 神经退行性疾病，所提出的实验可能具有广泛的临床意义。 我们最近表明，小胶质细胞的耗竭，刺激因子受体1 （CSFR1）拮抗剂PLX5622，导致WNV诱导的CNS疾病的严重程度增加 与CNS病毒滴度的增加有关。在该提案的特定目的1中，我们将使用PLX5622针对目标 小胶质细胞的消耗以确定小胶质细胞是否会影响病毒进入点的病毒生长 中枢神经系统，中枢神经系统内的病毒复制或病毒清除率。小胶质细胞功能以识别和删除入侵 通过吞噬细胞感染或受损细胞的病原体，用作抗原呈递细胞所需的细胞 通过分泌免疫调节分子产生完整的抗原特异性T细胞反应。在 特定目的2我们将确定小胶质细胞抑制WNV生长所需的哪些机制 在中枢神经系统中。 在特定目标3中，我们将确定小胶质细胞刺激作为治疗策略的疗效 WNV诱导的中枢神经系统疾病。对于这些研究，我们将使用粒细胞 - 巨噬细胞集落刺激因子 （GM-CSF），一种造血性生长因子和促炎细胞因子，可诱导，增殖和 激活小胶质细胞。重组人GM-CSF已经被FDA批准用于治疗白色 血细胞计数很低，例如某些类型的白血病或骨髓移植受者。 GM-CSF 目前正在研究与阿尔茨海默氏症有关的认知问题的潜在治疗方法 疾病。小鼠将接受重组人GM-CSF（白细胞）的治疗，并将受到监测以确定 病毒CNS滴度，病毒诱导的组织损伤和死亡以及神经后遗症在 幸存的老鼠。