"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

基本信息

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
项目类别：
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

项目摘要

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 - 西尼罗河过后“幸存者”神经元驱动持续炎症病毒感染西尼罗河病毒（WNV）是蚊媒黄病毒，可以感染中枢神经系统的神经元两种在神经侵袭性 WNV 中存活下来的人类患者小鼠模型生物体都表现出学习能力，记忆和运动后遗症在病毒被清除后仍持续很长时间。与中枢神经系统内的持续炎症有关，这种炎症的根源仍然存在我们小组和其他人之前的研究表明，神经元对这种现象具有独特的抵抗力。程序性细胞死亡是对多种应激源（包括病毒感染）的反应。小心那些被西尼罗河病毒感染但存活并清除感染的神经元——“幸存者”神经元—— 维持病毒引起的变化，导致长期炎症和中枢神经系统功能障碍。这个想法是通过创建表达 Cre 重组酶的 WNV 重组克隆，然后使用该病毒标记感染西尼罗河病毒的小鼠大脑中的“幸存者”神经元，对这些细胞进行空间转录组分析。研究表明，“幸存者”神经元在病毒感染几周后仍保持强大的炎症特征令人惊讶的是，同一组织内相邻的未经 WNV 处理的神经元中不存在这种特征。支持“幸存者”神经元是持续性中枢神经系统炎症的驱动因素这一观点。这里提出的是使用这个新开发的模型来首先了解“幸存者”神经元的变化导致持续炎症，其次评估这种炎症反应的后果我们认为这些神经元的功能、附近的细胞以及生物学习和记忆。这些新模型和新兴技术的使用将为中枢神经系统功能障碍提供重要的见解我们进一步表明这一见解可能适用于长期病毒引起的。其他情况下的炎症功能障碍。