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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：
10424785
负责人：
Veronica Anjali Dave
金额：
$ 6.76万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424785
关键词：
Acute Address Adult Affect Animals Astrocytes Attenuated Automobile Driving Biological Models Brain CASP1 gene Central Nervous System Viral Diseases Cognitive Cognitive deficits Data Defect Detection Disease Encephalitis Epidemic Exhibits Exposure to Flavivirus Functional disorder Hippocampus (Brain)Human Immune Immune response Immune system Impairment Infection Infection Control Inflammasome Inflammatory Injury Interferons Interleukin-1 beta Laboratories Learning Leukocytes Mediating Memory Microglia Modeling Molecular Monitor Mouse Strains Mus Mutation Neuraxis Neurocognitive Neurons Nucleotides Outcome Participant Pathologic Pathway interactions Pharmacology Production Proteins Purinergic P2 Receptors Purinoceptor RNA Viruses 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 Encephalitis West Nile viral infection West Nile virus experimental study extracellular in vivo learning ability macrophage mosquito-borne mouse model nerve stem cell neural correlate neurogenesis neurotropic novel 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特别困难的挑战免疫系统病毒必须从CNS中清除，而不会对CNS造成显著的免疫介导的损伤。神经组织近年来，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入性疾病（WNND），患有长期神经认知后遗症。过去我们实验室的研究通过直接接种减毒的West 尼罗河病毒进入第三脑室。在这个模型中，小鼠从脑炎中恢复，但免疫- 介导的损伤导致不利的认知后遗症。炎性星形胶质细胞在活化后产生白细胞介素-1 β 病毒感染和产生干扰素-γ的T细胞驱动小胶质细胞活化。每一种途径都是消极的影响海马突触恢复、海马神经发生和视觉空间学习。星形胶质细胞在体内不直接被西尼罗河病毒感染，但它们仍然显示NLRP 3 炎性小体活化和下游活性半胱天冬酶-1和白细胞介素-1 β的产生。的信号病毒感染期间星形胶质细胞中NLRP 3炎性体激活的驱动激活仍然完全未知然而，星形胶质细胞表达P2嘌呤能受体P2 RX 7，其可介导炎性小体，在暴露于高浓度细胞外ATP的巨噬细胞中活化。在这里，我建议神经元病毒性脑炎期间突触消除释放超生理水平的细胞外ATP，导致星形胶质细胞炎性小体激活。在目标1中，我将通过创造一部小说来证实这一假设。小鼠品系，其在星形胶质细胞上特异性且可诱导地缺乏P2 RX 7。此外，我建议加强细胞外ATP水平通过P2 RX 7向神经干细胞发出信号，驱动它们向反应性细胞分化，而不是神经发生。我推测，这条途径可能有助于缺乏在我们的WNND模型中海马神经发生。在目标2中，我将通过感染用西尼罗河病毒感染P2 RX 7缺陷型神经干细胞的动物，海马神经发生和视觉空间学习能力。总之，这些目标将表征新的嘌呤能受体P2 RX 7在神经侵袭性病毒感染过程中的功能，可能识别靶点用于降低感染后神经认知后遗症严重程度的药物治疗。