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.

病毒引起的中枢神经系统 (CNS) 疾病的治疗效果不佳或 不存在的。西尼罗河病毒（WNV）是美国流行性脑炎的最常见原因。这 该提案将研究小胶质细胞在中枢神经系统西尼罗河病毒感染过程中的作用，并评估小胶质细胞 刺激作为西尼罗河病毒引起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宿主强烈的神经炎症反应，包括 激活中枢神经系统免疫细胞（小胶质细胞）。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。它们可能在促进感染细胞的清除和感染细胞的恢复方面发挥保护作用。 受损的神经元。然而，小胶质细胞释放的许多因素可能会导致脑内损伤。 中枢神经系统。事实上，一般的神经炎症和特别是小胶质细胞的激活是关键的致病因素 神经系统损伤后以及非感染性神经系统和神经退行性病变期间的成分 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髓中的作用 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，拟议的实验可能会产生广泛的临床影响。 我们最近发现，小胶质细胞的耗竭与集落刺激因子受体 1 (CSFR1) 拮抗剂 PLX5622，导致小鼠 WNV 诱导的 CNS 疾病的严重程度增加 与中枢神经系统病毒滴度的增加有关。在此提案的具体目标 1 中，我们将使用 PLX5622 来定位 耗尽小胶质细胞以确定小胶质细胞是否在病毒进入病毒时影响病毒生长 CNS、CNS 内的病毒复制或病毒清除。小胶质细胞具有识别和清除入侵的功能 通过吞噬感染或受损的细胞，充当抗原呈递细胞来消灭病原体 产生完整的抗原特异性 T 细胞反应，并通过分泌免疫调节分子。在 具体目标 2 我们将确定小胶质细胞抑制 WNV 生长需要哪些机制 在中枢神经系统中。 在具体目标 3 中，我们将确定小胶质细胞刺激作为治疗策略的功效 西尼罗河病毒引起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 已获得 FDA 批准用于治疗白种人疾病 血细胞计数较低，例如某些类型的白血病或骨髓移植受者的血细胞计数较低。粒细胞集落刺激因子 目前正在研究作为与阿尔茨海默病相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（白细胞介素）治疗，并进行监测以确定 病毒中枢神经系统滴度、病毒引起的组织损伤和死亡以及神经系统后遗症的持续存在 幸存的老鼠。