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Mechanisms of neuronal injury during virus infection of the CNS

Mechanisms of neuronal injury during virus infection of the CNS
中枢神经系统病毒感染过程中神经元损伤的机制
批准号:
8076701
负责人:
Charles Lee Howe
金额:
$4.48万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-08-01 至 2013-05-31

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中文摘要
翻译
食源性和水传播的小核糖核酸病毒,如肠道病毒71是一个全球性的健康问题。神经系统 与神经毒性非脊髓灰质炎小核糖核酸病毒感染相关的并发症是一种严重的持续健康问题, 问题,尤其是儿童。不幸的是,小RNA病毒引起的中枢神经系统损伤的机制 中枢神经系统(CNS)不清楚。我们认为先天性免疫反应是导致 急性感染时神经元死亡。这与流行的假设相反,即神经元损失是 仅由病毒介导。虽然我们不怀疑一些神经元直接死于病毒感染, 我们的初步发现表明,某些群体,如海马体中的CA1锥体神经元, 是被先天免疫反应杀死的而不是被病毒杀死的。我们建立了一个小鼠模型, 使用Theiler小鼠脑脊髓炎病毒直接测试CNS的小核糖核酸病毒感染的作用, 中性粒细胞在神经元凋亡的启动。我们的初步证据表明,在急性 在CNS的小核糖核酸病毒感染中,许多未感染的CA 1锥体神经元经历与细胞凋亡相关的凋亡性死亡。 与氧化损伤,钙蛋白酶活性和半胱天冬酶活性;这种损伤严重降低认知能力, 空间记忆测试我们进一步观察到,中性粒细胞浸润海马在数小时内, 感染减少的中性粒细胞浸润是神经保护性的,而活化的中性粒细胞过继转移到 具有缺陷的中性粒细胞反应的小鼠诱导海马损伤。最后,用钙蛋白酶抑制剂治疗 保护海马神经元免于死亡,并保留认知功能,而不限制 炎症反应是介导宿主防御和病毒清除所必需的。根据这些 我们假设中性粒细胞通过钙蛋白酶依赖性机制杀死海马神经元 在中枢神经系统的急性小核糖核酸病毒感染期间。我们打算解决以下实验问题:1) 嗜中性粒细胞是否是杀死海马神经元的必要和充分条件?2)卡尔珀因是 海马神经元死亡诱导的中性粒细胞反应急性中枢神经系统感染?我们提出 几项创新,包括使用活体动物成像和过继转移中性粒细胞,以解决 这些问题。我们建议的关键概念是,虽然炎症严重介导宿主防御, 病毒感染时,炎症反应可能间接杀死神经元,因此治疗干预 旨在防止神经元死亡而不阻碍病毒的炎症控制的药物可以保护宿主功能。
英文摘要
Foodborne and waterborne picornaviruses such as enterovirus 71 are a global health issue. Neurologic complications associated with neurovirulent non-polio picornavirus infection are a serious ongoing health problem, especially in children. Unfortunately, the mechanisms of picornavirus-induced injury to the central nervous system (CNS) are unclear. We propose that the innate immune response is an important cause of neuron death during acute infection. This is in contrast to the prevailing hypothesis that neuron loss is mediated solely by virus. While we do not doubt that some neurons die directly as the result of viral infection, our preliminary findings suggest that certain populations, such as CA1 pyramidal neurons in the hippocampus, are killed by the innate immune response rather than by the virus. We have established a mouse model of picornavirus infection of the CNS using the Theiler's murine encephalomyelitis virus to directly test the role of neutrophils in the initiation of neuronal apoptosis. Our preliminary evidence indicates that during acute picornaviral infection of the CNS, many uninfected CA1 pyramidal neurons undergo apoptotic death associated with oxidative injury, calpain activity, and caspase activity; this injury severely reduces cognitive performance in a spatial memory test. We have further observed that neutrophils infiltrate the hippocampus within hours of infection. Reduced neutrophil infiltration is neuroprotective, while adoptive transfer of activated neutrophils into mice with a defective neutrophil response induces hippocampal injury. Finally, treatment with calpain inhibitors protects hippocampal neurons from death and preserves cognitive function without constraining the inflammatory response that is necessary to mediating host defense and viral clearance. On the basis of these observations we hypothesize that neutrophils kill hippocampal neurons via a calpain-dependent mechanism during acute picornaviral infections of the CNS. We intend to address the following experimental questions: 1) are neutrophils necessary and sufficient to kill hippocampal neurons?; 2) is calpain the key executioner of hippocampal neurons during death induced by the neutrophil response to acute CNS infection? We propose several innovations, including the use of live animal imaging and adoptive transfer of neutrophils, to address these questions. The key concept of our proposal is that while inflammation critically mediates host defense to virus infection, the inflammatory response may indirectly kill neurons, and therefore therapeutic interventions aimed at preventing neuronal death without thwarting inflammatory control of virus may preserve host function.
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Neuronal antigen surveillance and autoimmunity in CNS demyelinating disease
  • 批准号:
    10380683
  • 项目类别:
  • 资助金额:
    $59.47万
  • 财政年份:
    2020
  • 负责人:
    Charles Lee Howe
  • 依托单位:
Neuronal antigen surveillance and autoimmunity in CNS demyelinating disease
  • 批准号:
    10213156
  • 项目类别:
  • 资助金额:
    $59.47万
  • 财政年份:
    2020
  • 负责人:
    Charles Lee Howe
  • 依托单位:
Neuronal antigen surveillance and autoimmunity in CNS demyelinating disease
  • 批准号:
    10609862
  • 项目类别:
  • 资助金额:
    $59.2万
  • 财政年份:
    2020
  • 负责人:
    Charles Lee Howe
  • 依托单位:
Neuronal antigen surveillance and autoimmunity in CNS demyelinating disease
  • 批准号:
    10063399
  • 项目类别:
  • 资助金额:
    $59.47万
  • 财政年份:
    2020
  • 负责人:
    Charles Lee Howe
  • 依托单位:
海外基金