Investigating the interactions between viral infection, Tau pathology, and neuroinflammation

研究病毒感染、Tau 病理学和神经炎症之间的相互作用

• 批准号: 10746267
• 负责人: Kristen Emily Funk
• 金额: $ 128.1万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746267
• 关键词: Acceleration; Acute; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Attenuated; Brain; Cell Culture System; Data; Deposition; Development; Environment; Environmental Risk Factor; Exhibits; Exposure to; Extracellular Space; Flow Cytometry; Genes; Goals; Human; Immune response; Impaired cognition; Infection; Inflammation; Inflammatory Response; Kunjin virus; Link; MAPT gene; Measures; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroimmune; Neuroimmune system; Neurons; Pathogenesis; Pathology; Pattern; Phosphorylation; Phosphotransferases; Positioning Attribute; Process; Productivity; Proteins; Research; Risk; Risk Factors; Role; Senile Plaques; System; Testing; Transgenic Mice; Transgenic Organisms; Viral; Viral Encephalitis; Viral Load result; Virus; Virus Diseases; Virus Replication; West Nile virus; abeta accumulation; abeta deposition; antimicrobial peptide; cytokine; epidemiologic data; epidemiology study; experimental study; extracellular; hyperphosphorylated tau; in vivo; insight; microbial; mouse model; neuroinflammation; neuron loss; neurotropic; overexpression; pathogen; pathogenic bacteria; pathogenic virus; protein aggregation; response; tau Proteins; tau aggregation; tau interaction; tau-1; transcriptome sequencing

Project Summary Increasing evidence points to the neuroimmune system as a primary contributor to Alzheimer’s disease (AD). Environmental factors that increase neuroinflammation, including viral infections, correlate with risk of AD; however, the mechanisms by which microbial infections promote AD are not well understood. AD is defined by the presence of two hallmark pathologies—extracellular senile plaques composed of aggregated amyloid beta peptide (Aβ) and intracellular neurofibrillary tangles composed of the hyperphosphorylated microtubule associated protein tau. Recent studies have suggested that Aβ may act as an antimicrobial peptide, in which its aggregation can restrict microbial infection by trapping it in the extracellular space. We hypothesize that as an intracellular protein, Tau may act as an antimicrobial peptide against viruses, which are obligate intracellular pathogens. Our preliminary data shows that following intracranial inoculation with an attenuated strain of West Nile virus, Kunjin virus (KUNV), Tau becomes hyperphosphorylated and aggregates. Furthermore, transgenic mice expressing elevated levels of aggregation-prone Tau show reduced viral burden in their brains. Here we propose to study the interactions between viral infection, Tau pathology, and neuroinflammation using a murine model of encephalitic KUNV infection. Aim 1 will determine whether viral infection increases Tau pathology by measuring aggregation, phosphorylation, and truncation. Aim 2 will assess the impact of Tau aggregation on viral replication and whether Tau interacts directly with viral components. Aim 3 will examine the effect of Tau pathology on the neuroinflammatory response to viral infection. Together, these experiments will determine whether viral infection impacts the development of Tau pathology and the role of Tau pathology in modulating the neuroimmune response to viral infection. Successful completion of this project will establish a mechanistic link between AD and viral pathogens.

项目摘要 越来越多的证据表明，神经免疫系统是阿尔茨海默病（AD）的主要贡献者。 增加神经炎症的环境因素，包括病毒感染，与AD的风险相关; 然而，微生物感染促进AD的机制尚不清楚。AD定义为 存在两种标志性病理学-由聚集的淀粉样蛋白β组成的细胞外老年斑 肽（Aβ）和由过度磷酸化微管组成的细胞内神经原纤维缠结 相关蛋白tau。最近的研究表明，Aβ可能是一种抗菌肽，其中 它的聚集可以通过将其捕获在细胞外空间来限制微生物感染。我们假设， Tau是一种细胞内蛋白，可以作为抗病毒的抗菌肽， 病原体我们的初步数据表明，颅内接种西尼罗病毒减毒株后， 尼罗河病毒、昆津病毒（KUNV），Tau变得过度磷酸化并聚集。此外，转基因 表达高水平的易聚集Tau的小鼠显示其脑中的病毒负荷降低。这里我们 建议使用小鼠模型研究病毒感染、Tau病理学和神经炎症之间的相互作用。 脑炎KUNV感染模型。目的1将通过以下方式确定病毒感染是否增加Tau病理学： 测量聚集、磷酸化和截短。目标2将评估Tau聚集对 病毒复制以及Tau是否直接与病毒组分相互作用。目标3将检查Tau的效果 病毒感染引起的神经炎症反应的病理学。这些实验将决定 病毒感染是否影响Tau病理学的发展以及Tau病理学在调节Tau病理学中的作用 对病毒感染的神经免疫反应该项目的成功完成将建立一个机制， AD和病毒病原体之间的联系。