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.

项目摘要中枢神经系统（CNS）的病毒感染对宿主构成了一个特别困难的挑战免疫系统。必须从中枢神经系统中清除病毒，而没有明显的免疫介导的损害神经组织。近年来，人们越来越认识到病毒性脑膜的存活，例如西尼罗河病毒神经侵袭性疾病（WNND），患有长期神经认知后遗症。过去的我们实验室的研究通过直接接种减毒的西部进行了对小鼠现象的建模尼罗河病毒进入大脑的第三个心室。在该模型中，小鼠从脑炎中恢复过来，但免疫介导的损害导致不良认知后遗症。炎性星形胶质细胞在病毒感染和产生干扰素的T细胞驱动小胶质细胞激活。这些途径中的每一个负面影响海马突触恢复，海马神经发生和视觉学习。星形胶质细胞不直接被体内西尼罗河病毒感染，但它们仍然显示NLRP3 活性caspase-1和白介素1β的炎性体激活和下游产生。信号病毒感染期间星形胶质细胞中NLRP3炎症体激活的驱动激活仍然完全未知。但是，星形胶质细胞表达P2嘌呤能受体P2RX7，可以介导炎性体暴露于高浓度细胞外ATP的巨噬细胞中的激活。在这里，我建议神经元病毒性脑炎期间的突触消除释放细胞外ATP的上术水平，导致星形胶质细胞炎症体激活。在AIM 1中，我将寻求通过产生小说来确认这一假设小鼠应变，特定诱导的人星形胶质细胞缺乏P2RX7。此外，我建议提高细胞外ATP水平通过P2RX7信号向神经元干细胞发出信号，将其分化向反应性驱动天气生成而不是神经发生。我假设该途径可能有助于缺乏我们的WNND模型中的海马神经发生。在AIM 2中，我将通过感染来调查这种可能性具有P2RX7缺乏性神经干细胞的动物，西尼罗河病毒并监测变化海马神经发生和视觉学习能力。这些目标在一起将描述小说神经侵染病毒感染期间嘌呤能受体P2RX7的功能，有可能识别靶标用于减少感染后神经认知后遗症严重程度的药物疗法。