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

基本信息

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
项目类别：
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

项目摘要

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）：食源性和水源性小核糖核酸病毒（例如肠道病毒 71）是一个全球性健康问题。与神经毒性非脊髓灰质炎小核糖核酸病毒感染相关的神经系统并发症是一个严重的持续健康问题，尤其是对于儿童。不幸的是，小核糖核酸病毒引起的中枢神经系统（CNS）损伤的机制尚不清楚。我们认为先天免疫反应是急性感染期间神经元死亡的重要原因。这与神经元损失仅由病毒介导的流行假设形成鲜明对比。虽然我们并不怀疑某些神经元会因病毒感染而直接死亡，但我们的初步研究结果表明，某些群体，例如海马体中的 CA1 锥体神经元，是被先天免疫反应而不是病毒杀死的。我们使用泰勒氏鼠脑脊髓炎病毒建立了中枢神经系统小核糖核酸病毒感染的小鼠模型，以直接测试中性粒细胞在启动神经元凋亡中的作用。我们的初步证据表明，在中枢神经系统急性小核糖核酸病毒感染期间，许多未感染的 CA1 锥体神经元经历与氧化损伤、钙蛋白酶活性和半胱天冬酶活性相关的细胞凋亡。这种损伤严重降低了空间记忆测试中的认知能力。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。中性粒细胞浸润减少具有神经保护作用，而将活化的中性粒细胞过继转移到中性粒细胞反应缺陷的小鼠体内会引起海马损伤。最后，钙蛋白酶抑制剂治疗可保护海马神经元免于死亡并保留认知功能，而不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急性小核糖核酸病毒感染期间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）中性粒细胞是否足以杀死海马神经元？ 2）钙蛋白酶是中性粒细胞对急性中枢神经系统感染反应引起的海马神经元死亡过程中的关键执行者吗？我们提出了多项创新来解决这些问题，包括使用活体动物成像和中性粒细胞过继转移。我们建议的关键概念是，虽然炎症关键介导宿主对病毒感染的防御，但炎症反应可能间接杀死神经元，因此旨在预防神经元死亡而不阻碍病毒炎症控制的治疗干预可能会保留宿主功能。公共卫生相关性：某些食源性和水源性病毒能够感染大脑。尽管成人易感，但儿童尤其容易遭受此类神经毒性感染。我们从小鼠模型中得到的证据表明，认知功能随着海马神经元的死亡而丧失。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 批准的药物治疗可以保护神经元和认知功能，而不会改变免疫系统清除大脑中病毒的能力。