"Survivor" neurons drive persistent inflammation following West Nile virus infection

西尼罗河病毒感染后，“幸存者”神经元驱动持续炎症

• 批准号: 10731043
• 负责人: Andrew Atwell Oberst
• 金额: $ 26.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-18 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731043
• 关键词: ATAC-seq; Address; Apoptosis; Arboviruses; Brain; Cell Death; Cell Survival; Cells; Central Nervous System; Cognition; Cognitive; Cognitive deficits; Complex; Defect; Disease; Emerging Technologies; Encephalitis; Enterobacteria phage P1 Cre recombinase; Epigenetic Process; Family; Flaviviridae; Flavivirus; Functional disorder; Gene Expression Profile; Genes; Goals; Hippocampus; Human; Immune response; Immune signaling; Immune system; Impaired cognition; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Learning; Mediating; Memory; Memory impairment; Modeling; Motor; Mus; Neighborhoods; Neuroglia; Neurons; Organism; Pathology; Pathway interactions; Patients; Peptide Initiation Factors; Property; Public Health; Recombinants; Recovery; Research; Resistance; Role; Signal Pathway; Signal Transduction; Source; Stimulus; Suicide; Survivors; System; Techniques; Testing; Tissues; Viral; Virus; Virus Diseases; West Nile Encephalitis; West Nile viral infection; West Nile virus; Work; insight; model organism; mortality; mosquito-borne; mouse model; neuronal survival; neurotropic virus; novel; pathogen; postmitotic; preservation; response; stressor; transcriptomics; viral genomics

Project Summary/Abstract- “Survivor” neurons drive persistent inflammation following West Nile virus infection West Nile virus (WNV) is mosquito-borne flavivirus that can infect neurons of the central nervous system. Both human patients murine model organisms that survive neuroinvasive WNV display learning, memory and motor sequelae that persist long after the virus is cleared. While these sequelae have been associated with persistent inflammation within the CNS, the source of this inflammation has remained obscure. Previous studies by our group and others have revealed that neurons are remarkably resistant to programmed cell death in response to multiple stressors, including viral infection. This observation led us to hypothesize that neurons that are infected with WNV but survive and clear infection—“survivor” neurons— sustain virus-induced changes that drive long-term inflammation and CNS disfunction. We sought to test this idea by creating a recombinant clone of WNV that expresses Cre recombinase, then using this virus to mark “survivor” neurons in the brains of WNV-infected mice. Spatial transcriptomic analysis of these cells revealed that “survivor” neurons maintain a robust inflammatory signature weeks after viral infection is cleared. Strikingly, this signature is absent in adjacent, WNV-naïve neurons within the same tissues, supporting the idea that “survivor” neurons are drivers of persistent CNS inflammation. The goal of the work proposed here is to use this newly-developed model to first understand the changes to “survivor” neurons that drive persistent inflammation, and second to assess the consequences of this inflammatory response on the function of these neurons, on nearby cells and on organismal learning and memory. We suggest that the use of these new models and emerging technologies will provide important insight into CNS disfunction caused by WNV infection. We further suggest that this insight may be applicable to long-term virus-induced inflammatory dysfunction in other settings.

项目摘要/摘要-“幸存者”神经元在西尼罗河病毒感染后驱动持续性炎症 病毒感染 西尼罗河病毒是一种蚊媒黄病毒，可感染中枢神经系统的神经元 系统在神经侵入性西尼罗河病毒中生存的两名人类患者鼠模型生物都表现出学习能力， 记忆和运动后遗症，在病毒清除后仍会持续很长时间。虽然这些后遗症已经 与CNS内的持续性炎症相关，这种炎症的来源仍然存在 晦涩难懂。我们小组和其他人以前的研究表明，神经元对 程序性细胞死亡是对包括病毒感染在内的多种应激源的反应。这一观察使我们 假设被WNV感染但存活并清除感染的神经元-“幸存者”神经元- 持续病毒诱导的变化，驱动长期炎症和CNS功能障碍。我们试图测试 通过创建表达Cre重组酶的WNV重组克隆，然后使用该病毒， 在WNV感染的小鼠大脑中标记“幸存者”神经元。这些细胞的空间转录组学分析 揭示了“幸存者”神经元在病毒感染后几周内保持着强大的炎症信号， 通关令人惊讶的是，在同一组织中的相邻的WNV-幼稚神经元中不存在这种特征， 这支持了“幸存者”神经元是持续性CNS炎症的驱动因素的观点。工作目标 这里提出的是使用这个新开发的模型，首先了解“幸存者”神经元的变化 第二，评估这种炎症反应的后果， 对这些神经元的功能，对附近的细胞，对有机体的学习和记忆。我们建议 这些新模型和新兴技术的应用将为研究中枢神经系统功能障碍提供重要的信息 由西尼罗河病毒感染引起。我们进一步认为，这种见解可能适用于长期病毒诱导的 炎症性功能障碍。