Protection of Mice From Lethal Alphavirus Encephalitis

保护小鼠免受致命甲病毒脑炎的侵害

• 批准号: 7666293
• 负责人: DAVID N IRANI
• 金额: $ 28.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666293
• 关键词: Acute; Affect; Alphavirus; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Anti-Inflammatory Agents; Antiviral Agents; Arboviruses; Attenuated; Bioterrorism; Bite; Brain; Candidate Disease Gene; Categories; Cell Death; Cells; Cessation of life; Clinical; Diagnosis; Disease; Dose; Encephalitis; Encephalomyelitis; Flavivirus; Future; Gene Expression; Hindlimb; Human; Immune response; In Vitro; Individual; Infection; Inflammatory; Injury; Intervention; Intraperitoneal Injections; Ischemic-Hypoxic Encephalopathy; Mediating; Methodology; Microarray Analysis; Microglia; Minocycline; Modeling; Multiple Sclerosis; Mus; Naloxone; Nerve Degeneration; Neuraxis; Neurologic; Neuronal Injury; Neurons; Neuroprotective Agents; Opioid Receptor; Outcome; Paralysed; Pathogenesis; Pattern; Pharmaceutical Preparations; Poliomyelitis; Population; Process; Protective Agents; Public Health; Research Personnel; Safety; Sindbis Virus; Spinal Cord; Suggestion; Tetracyclines; Therapeutic; Tissues; Treatment Protocols; United States; United States Public Health Service; Vaccines; Viral; Viral Pathogenesis; Virus; West Nile virus; cDNA Arrays; clinical effect; in vivo; large scale production; macrophage; mature animal; neurotoxicity; neurovirulence; pathogen; programs; tool; vector mosquito

DESCRIPTION (provided by applicant): Alphaviruses are important causes of fatal encephalitis in humans worldwide. Many are also designated as Category B Priority Pathogens by the U.S. Public Health Service given their potential use as bioterrorism agents. One alphavirus, Sindbis virus (SV), has been extensively studied in a murine model. In particular, a neuroadapted strain (NSV) induces a highly reproducible disease in susceptible hosts with hindlimb paralysis and death that evolves over a period of 7-10 days. All strains of SV target neurons in the brain and spinal cord, and the fate of these cells determines neurovirulence. Further, non-infected neurons are also damaged via bystander mechanisms, and host immune responses have now been implicated in this aspect of viral pathogenesis. We know that microglia, the endogenous macrophage-like cell of the central nervous system (CNS), become activated soon after NSV infection, and we now show that two unrelated drugs that inhibit this microglial activation process also protect mice from NSV-induced hindlimb paralysis and death without exerting any effect on CNS viral replication or spread. In order to study this unique form of protection against NSV encephalomyelitis in greater detail, we propose: (1) To further characterize the beneficial effects of neuroprotective drugs in NSV-infected mice using treatment regimens where dosing begins only at or after the onset of overt neurologic disease, to characterize the effects of other anti-inflammatory agents known to target microglia in our model, and to verify the effects of all our protective agents against other New World alphaviruses that cause fatal encephalitis in humans, (2) To investigate histopathological correlates of drug-mediated protection from NSV-induced hindlimb paralysis and death, and to further characterize how each drug affects microglial activation in the CNS in vivo and microglial-induced injury of primary neurons iin vitro, (3) To compare temporal patterns of gene expression in purified tissue microglia from NSV-infected animals with or without protective drug treatment using cDNA microarray methodologies, and (4) To functionally characterize candidate genes identified by cDNA microarray analysis that are modulated by protective drug treatment regimens and to determine whether these candidates contribute to NSV pathogenesis in vivo and to microglial-induced neurotoxicity in vitro.

描述（由申请人提供）：甲病毒是全世界人类致命性脑炎的重要原因。鉴于它们可能用作生物恐怖主义制剂，许多病原体还被美国公共卫生服务部门指定为 B 类优先病原体。一种甲病毒，即辛德比斯病毒（SV），已在小鼠模型中进行了广泛研究。特别是，神经适应菌株（NSV）会在易感宿主中诱发高度可重复的疾病，导致后肢麻痹和死亡，该疾病会在 7-10 天内进化。所有 SV 菌株都以大脑和脊髓中的神经元为目标，这些细胞的命运决定了神经毒力。此外，未感染的神经元也会通过旁观者机制受到损害，宿主免疫反应现在与病毒发病机制的这一方面有关。我们知道，小胶质细胞是中枢神经系统（CNS）的内源性巨噬细胞样细胞，在 NSV 感染后很快就会被激活，现在我们发现，抑制这种小胶质细胞激活过程的两种不相关的药物也能保护小鼠免受 NSV 诱导的后肢麻痹和死亡，而不会对 CNS 病毒复制或传播产生任何影响。为了更详细地研究这种独特的针对 NSV 脑脊髓炎的保护形式，我们建议：（1）进一步表征神经保护药物对 NSV 感染小鼠的有益作用，使用仅在明显神经系统疾病发作时或发病后开始给药的治疗方案，表征已知针对我们模型中小胶质细胞的其他抗炎药物的作用，并验证我们所有保护性药物的作用。 对抗引起人类致命性脑炎的其他新大陆甲病毒的药物，(2) 研究药物介导的防止 NSV 诱导的后肢麻痹和死亡的保护作用的组织病理学相关性，并进一步表征每种药物如何影响中枢神经系统体内小胶质细胞激活和体外小胶质细胞诱导的初级神经元损伤，(3) 比较基因表达的时间模式 使用cDNA微阵列方法从经或未经保护性药物治疗的NSV感染动物中纯化组织小胶质细胞，以及（4）功能性地表征通过cDNA微阵列分析鉴定的候选基因，这些候选基因由保护性药物治疗方案调节，并确定这些候选基因是否有助于体内NSV发病机制和体外小胶质细胞诱导的神经毒性。