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: 8268556
• 负责人: Charles Lee Howe
• 金额: $ 29.15万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268556
• 关键词: Acute; Address; Adoptive Transfer; Adult; Animals; Apoptotic; Ataxia; Biological Phenomena; Brain; Calcium; Calpain; Caspase; Cell Death; Cells; Central Nervous System Infections; Central Nervous System Viral Diseases; Cessation of life; Child; Cognitive; Complex; Coupled; Disease Outbreaks; Employee Strikes; Enterovirus 71; Equilibrium; FDA approved; Family Picornaviridae; Health; Hippocampus (Brain); Host Defense; Hour; Human; Image; Immune; Immune response; Immune system; Impaired cognition; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Life; Mediating; Memory; Modeling; Mus; Neuraxis; Neurologic; Neuronal Injury; Neurons; Neutrophil Infiltration; Peptide Hydrolases; Performance; Pharmaceutical Preparations; Picornaviridae Infections; Population; Risk; Role; Seizures; TMEV; Testing; Therapeutic Intervention; Uncertainty; Viral; Virus; Virus Diseases; Work; base; calpain inhibitor; cognitive function; foodborne; global health; hippocampal pyramidal neuron; immunopathology; innovation; killings; mouse model; neuron apoptosis; neuron loss; neurotoxic; neutrophil; novel therapeutics; prevent; response; trafficking; waterborne

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Certain foodborne and waterborne viruses have the ability to infect the brain. Although adults are susceptible, children are at particular risk for such neurovirulent infections. We have evidence from a mouse model that cognitive function is lost concomitantly with the death of hippocampal neurons. We also have evidence that this neuronal death is caused by a specific population of immune cells called neutrophils that are trying to clear the virus from the brain. Importantly, we have found that treatment with an FDA-approved drug protects neurons and cognitive function without altering the ability of the immune system to clear the virus from the brain.

描述（由申请人提供）：诸如肠病毒71之类的食源性和水源性皮质病毒是全球健康问题。与神经性非Polio picornavirus感染相关的神经系统并发症是严重的健康问题，尤其是在儿童中。不幸的是，尚不清楚Picornavirus诱导的中枢神经系统损伤的机制尚不清楚。我们建议先天免疫反应是急性感染期间神经元死亡的重要原因。这与普遍的假设相反，即神经元丧失仅由病毒介导。尽管我们毫不怀疑某些神经元直接死于病毒感染，但我们的初步发现表明，某些人群（例如海马中的CA1锥体神经元）被先天免疫反应杀死，而不是病毒。我们已经使用Theiler的鼠脑脊髓炎病毒建立了CNS的小鼠Picornavirus感染的小鼠模型，以直接测试中性粒细胞在启动神经元细胞凋亡中的作用。我们的初步证据表明，在中枢神经系统的急性picornaviral感染期间，许多未感染的CA1锥体神经元会经历与氧化损伤，钙蛋白酶活性和caspase活性相关的凋亡死亡。这种伤害在空间记忆测试中严重降低了认知性能。我们进一步观察到，中性粒细胞在感染后数小时内浸润海马。嗜中性粒细胞浸润的降低是神经保护作用，而活化的中性粒细胞的产卵转移到具有缺陷的中性粒细胞反应的小鼠中会诱导海马损伤。最后，用钙蛋白酶抑制剂治疗可保护海马神经元免受死亡的影响，并保留认知功能，而无需限制介导宿主防御和病毒清除所必需的炎症反应。根据这些观察结果，我们假设中性粒细胞在中枢神经系统的急性picornaviral感染过程中通过钙蛋白酶依赖性机制杀死海马神经元。我们打算解决以下实验问题：1）中性粒细胞是否需要杀死海马神经元？ 2）Calpain是中性粒细胞对急性中枢神经系统感染的反应引起的海马神经元的关键执行者吗？我们提出了几项创新，包括使用现场动物成像和中性粒细胞的收养转移来解决这些问题。我们建议的关键概念是，尽管炎症严重介导了宿主防御病毒感染，但炎症反应可能会间接杀死神经元，因此旨在防止神经元死亡而不会阻止炎症控制病毒功能的治疗干预措施可能会保留宿主功能。公共卫生相关性：某些食源性和水生病毒具有感染大脑的能力。尽管成年人易受感染，但儿童特别有这种神经性肺部感染的风险。我们有来自小鼠模型的证据表明，认知功能与海马神经元死亡同时丧失。我们还有证据表明，这种神经元死亡是由一种称为中性粒细胞的特定免疫细胞群引起的，这些免疫细胞试图从大脑中清除病毒。重要的是，我们发现使用FDA批准的药物进行治疗可保护神经元和认知功能，而不会改变免疫系统清除大脑病毒的能力。