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Neurotropic Viral Infection in CNS Aging and Alzheimer's Disease COVID-19 Supplement

中枢神经系统衰老和阿尔茨海默病中的神经病毒感染 COVID-19 补充剂

基本信息

批准号：
10188852
负责人：
Kristen Emily Funk
金额：
$ 24.39万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188852
关键词：
2019-nCoV Acute Address Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid beta-Protein Antiviral Response Apoptosis Behavioral Blood - brain barrier anatomy Brain COVID-19 Cells Cellular Immunity Central Nervous System Diseases Central Nervous System Infections Chronic Cognitive Coronavirus Coronavirus Infections Data Delirium Dementia Deposition Development Disease Elderly Event Functional disorder Gene Expression Goals Healthcare Hepatic Immune Immune system Impaired cognition In Vitro Individual Infection Inflammation Inflammatory Intensive Care Units Lower Respiratory Tract Infection MAPT gene Measures Memory Loss Microglia Modeling Molecular Murine hepatitis virus Mus Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurologic Symptoms Neurons Neurotropism Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Patients Phase Population Predisposition Process RNA Viruses Recovery Reporting Research Risk Risk Factors Severities Systemic infection Testing Transgenic Mice Viral Viral Encephalitis Viral Pneumonia Virus Virus Diseases Virus Replication West Nile viral infection West Nile virus Wild Type Mouse aged antiviral immunity cytokine experimental study functional decline immune function improved in vivo mouse model neuroinflammation neuron loss neurotropic pandemic disease pathogenic virus response systemic inflammatory response tau Proteins tau aggregation

项目摘要

Project Summary The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resulting disease (COVID-19) emerged as an unprecedented worldwide healthcare crisis. COVID-19 primarily manifests as a lower respiratory tract infection and viral pneumonia; however, neurotropism is a common feature of coronaviruses (CoVs) and has been documented for almost all betacoronaviruses, the clade to which SARS-CoV-2 belongs. It was reported that 36% of COVID-19 patients develop neurologic symptoms, but whether these are due to CNS infection, systemic inflammatory response, or intensive care unit delirium is unknown. Advanced age is a significant risk factor for developing severe infection from SARS-CoV-2. Aging is associated with compromised cellular immunity and blood brain barrier dysfunction, which may increase the vulnerability of the CNS to infection and long-term damage from systemic infections. Neuroinflammation is recognized as contributing to disorders of the central nervous system (CNS) including Alzheimer’s disease (AD). Our overarching hypothesis is that viral encephalitis enhances inflammatory events that accelerate CNS aging processes and contribute to the development of AD pathology. The original application proposed to use West Nile virus (WNV) as a model of viral encephalitis to examine behavioral, cellular, and molecular mechanisms of CNS recovery. Here we propose to enhance this research by investigating a murine CoV model, mouse hepatitis virus A-59. Like WNV, CoVs are enveloped positive-stranded RNA viruses, but have distinct effects in the CNS. The addition of this CoV model will augment the original scope of the proposal by allowing the comparison of results from each of the two models to determine universal aging processes that result from viral infection. In this supplement, we propose to test the hypothesis that advanced age increases the risk of lethal neurotropic infection by CoV and that inflammatory processes initiated by infection may contribute to the pathogenesis of AD. Aim 1 will determine the impact of advanced age on acute viral infection and antiviral response. Aim 2 will identify the effect of advanced age on microglial response to infection. Aim 3 will investigate the impact of viral encephalitis on pathological Tau accumulation. These studies will address the urgent need to understand how aging impacts CoV infections, the impact of viral encephalitis on aging processes in the CNS, and their contribution to neurodegenerative diseases. The experiments proposed here will be analyzed in parallel with our established model of WNV to enhance the goals of the original proposal.

项目摘要由严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）引起的全球大流行及其由此产生的疾病（COVID-19）成为前所未有的全球医疗危机。COVID-19主要表现为下呼吸道感染和病毒性肺炎;然而，嗜神经性是常见的冠状病毒（CoV）的特征，并已记录了几乎所有的β冠状病毒，进化枝， SARS-CoV-2属于哪种病毒据报道，36%的COVID-19患者会出现神经系统症状，但无论这些是由于中枢神经系统感染，全身炎症反应，或重症监护病房谵妄，未知高龄是严重感染SARS-CoV-2的重要危险因素。衰老是与受损的细胞免疫和血脑屏障功能障碍有关，这可能会增加 CNS对感染的脆弱性和来自全身性感染的长期损害。神经炎症并被认为是导致中枢神经系统（CNS）紊乱的原因，包括阿尔茨海默病（AD）。我们的总体假设是病毒性脑炎会增强炎症事件，从而加速中枢神经系统衰老过程，并有助于AD病理学的发展。最初的申请建议使用西尼罗河病毒（WNV）作为病毒性脑炎的模型，以检查行为，细胞和分子中枢神经系统的恢复机制。在这里，我们建议通过调查小鼠冠状病毒来加强这项研究模型，小鼠肝炎病毒A-59。像西尼罗河病毒一样，CoV是有包膜的正链RNA病毒，但具有对CNS的影响。增加这一CoV模型将扩大提案的原始范围，允许比较来自两个模型中的每一个的结果以确定普遍的老化过程，是病毒感染的结果。在这篇增刊中，我们提出检验高龄增加的假设，由CoV引起致死性嗜神经性感染的风险和由感染引发的炎症过程可能有助于AD的发病机制。目的1将确定高龄对急性病毒感染的影响和抗病毒反应。目的2将确定高龄对小胶质细胞感染反应的影响。目标3 将研究病毒性脑炎对病理性Tau积累的影响。这些研究将解决迫切需要了解衰老如何影响CoV感染，病毒性脑炎对衰老的影响，过程中的中枢神经系统，以及它们的贡献神经退行性疾病。这里提出的实验将与我们建立的WNV模型并行分析，以增强原始提案的目标。