Mechanisms and impacts of astrocyte inflammasome activation during viral encephalitis

病毒性脑炎期间星形胶质细胞炎症小体激活的机制和影响

基本信息

批准号：
10704530
负责人：
Veronica Anjali Dave
金额：
$ 4.08万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-01-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10704530
关键词：
Acute Address Affect Animals Astrocytes Attenuated Automobile Driving Biological Models Brain CASP1 gene Central Nervous System Central Nervous System Viral Diseases Cognitive Cognitive deficits Data Defect Detection Disease Encephalitis Exhibits Exposure to Flavivirus Functional disorder Hippocampus Human Immune Immune response Immune system Impairment In Vitro Infection Inflammasome Inflammatory Injury Interferon Type II Interferons Interleukin-1 beta Laboratories Learning Leukocytes LoxP-flanked allele Macrophage Mediating Memory Microglia Modeling Molecular Monitor Mouse Strains Mus Mutation Neurocognitive Neurons Nucleotides Outcome Participant Pathologic Pathway interactions Production Proteins Purinergic P2 Receptors Purinoceptor RNA Viruses Receptor Signaling Recovery Research Role Severities Signal Transduction Source Survivors Synapses T cell response T-Lymphocyte Third ventricle structure Tissues Viral Viral Encephalitis Virus Virus Diseases Visuospatial West Nile West Nile Encephalitis West Nile viral infection West Nile virus adult neurogenesis astrocyte progenitor epidemic virus experimental study extracellular in vivo learning ability mosquito-borne mouse model nerve stem cell neural circuit neural correlate neurogenesis neurotropic novel pharmacologic prevent receptor recruit response stem cell fate therapeutic target viral RNA

项目摘要

PROJECT SUMMARY Viral infections of the central nervous system (CNS) pose a particularly difficult challenge to the host immune system. Virus must be cleared from the CNS without significant immune-mediated damage to neuronal tissues. In recent years, it has been increasingly recognized that survivors of viral encephalitides, such as West Nile virus neuroinvasive disease (WNND), suffer from longterm neurocognitive sequelae. Past research from our laboratory has modeled this phenomenon in mice by direct inoculation of attenuated West Nile virus into the third ventricle of the brain. In this model, mice recover from encephalitis, but immune- mediated damage causes adverse cognitive sequelae. Inflammatory astrocytes produce interleukin-1β after viral infection and interferon-γ-producing T cells drive microglia activation. Each of these pathways negatively impacts hippocampal synapse recovery, hippocampal neurogenesis, and visuospatial learning. Astrocytes are not directly infected by West Nile virus in vivo, but they nonetheless display NLRP3 inflammasome activation and downstream production of active caspase-1 and interleukin-1β. The signals that drive activation of the NLRP3 inflammasome activation in astrocytes during viral infection remain completely unknown. However, astrocytes express the P2 purinergic receptor P2RX7, which can mediate inflammasome activation in macrophages exposed to high concentrations of extracellular ATP. Here, I propose that neuronal synapse elimination during viral encephalitis releases supraphsyiologic levels of extracellular ATP, leading to astrocyte inflammasome activation. In Aim 1, I will seek to confirm this hypothesis by generating a novel mouse strain that specifically and inducibly lacks P2RX7 on astrocytes. In addition, I propose that heightened extracellular ATP levels signal to neuronal stem cells via P2RX7, driving their differentiation towards reactive astrogenesis rather than neurogenesis. I hypothesize that this pathway may contribute towards the lack of hippocampal neurogenesis in our model of WNND. In Aim 2, I will investigate this possibility by infecting animals with P2RX7-deficient neural stem cells with West Nile virus and monitoring for changes in hippocampal neurogenesis and visuospatial learning ability. Together, these Aims will characterize novel functions of the purinergic receptor P2RX7 during neuroinvasive viral infection, potentially identifying a target for pharmacologic therapies that reduce the severity of post-infectious neurocognitive sequelae.

项目概要中枢神经系统（CNS）的病毒感染对宿主构成了特别困难的挑战病毒必须从中枢神经系统中清除，而不会对免疫系统造成重大损害。近年来，人们越来越认识到病毒性脑炎的幸存者，例如西尼罗河病毒神经侵袭性疾病（WNND），患有长期的神经认知后遗症。我们实验室的研究通过直接接种减毒Western在小鼠中模拟了这种现象在这个模型中，尼罗河病毒进入大脑的第三脑室，小鼠从脑炎中恢复过来，但免疫系统介导的损伤会导致不良的认知后遗症炎症性星形胶质细胞在产生白细胞介素-1β后。病毒感染和产生干扰素 γ 的 T 细胞会驱动小胶质细胞激活。影响海马突触恢复、海马神经发生和视觉空间学习。星形胶质细胞在体内并未直接被西尼罗河病毒感染，但它们仍然显示NLRP3 炎症小体激活和下游产生活性 caspase-1 和 interleukin-1β 的信号。病毒感染期间星形胶质细胞中 NLRP3 炎症小体的驱动激活完全保持不变然而，星形胶质细胞表达 P2 嘌呤能受体 P2RX7，它可以介导炎症小体。暴露于高浓度细胞外 ATP 的巨噬细胞的激活在这里，我提出神经元。病毒性脑炎期间的突触消除释放细胞外 ATP 的超神经水平，导致在目标 1 中，我将通过生成一个新的模型来证实这一假设。星形胶质细胞上特异性地诱导性缺乏 P2RX7 的小鼠品系此外，我建议氧气。细胞外 ATP 水平通过 P2RX7 向神经干细胞发出信号，驱动它们向反应性分化我认为这条途径可能导致星体发生而不是神经发生。在我们的 WNND 模型中，我将通过感染来研究这种可能性。具有 P2RX7 缺陷神经干细胞的动物与西尼罗河病毒并监测海马神经发生和视觉空间学习能力共同构成了新的目标。嘌呤能受体 P2RX7 在神经侵袭性病毒感染期间的功能，可能确定目标用于减轻感染后神经认知后遗症严重程度的药物治疗。