Intersection of HSV-1 and microglial genetics in AD

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种与年龄相关的神经退行性疾病，以进行性认知功能障碍为特征 衰退和痴呆。全基因组关联研究已经确定了新的AD易感基因座。有趣的 在这些基因座中的几个位点上的相关基因暗示了晚发性AD中的免疫系统，特别是 先天免疫系统最近的许多证据表明，免疫系统在AD中起着关键作用 启动和进展，但实际的机械功能障碍的免疫系统在这一点上， 神经退行性疾病仍然未知。遗传学研究和病理学暗示免疫系统 在AD中，已经丧失了进行生产性反应的能力，并产生了有害的后果。验尸 AD患者的病理学揭示了T细胞在海马体中的浸润，该区域预期是 免疫特权，导致推测AD可能具有其病因学的感染性成分， 进展与此同时，病原体假说已经获得了更多的支持，一个可能的致病病因 的AD。我们建议利用我们对免疫系统的理解来确定免疫反应是否 神经侵袭性病原体人类单纯病毒（HSV）-1受AD遗传关联调节，导致 增加AD的风险。我们将采取全面的方法，使用尖端工具来探索这一点 AD中的假设结合遗传学，人类免疫学，转录组学，病毒学，体外模型， 计算生物学和流行病学，我们将剖析HSV-1感染和AD之间的相互作用 遗传学对于这个应用程序，我们提出了一个多方面的方法，使用尖端技术：1）识别 根据每个人的遗传背景，小胶质细胞对HSV-1感染的反应; 2）检查这些反应如何发生。 小神经胶质细胞作为抗原呈递细胞作用于T细胞，T细胞是解决活动性感染的关键细胞类型;以及3） 在两个已建立的队列和一项抗病毒临床试验中确定HSV-1和AD遗传学的相互作用 在AD中。

Project Summary Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Genome-wide association studies have identified novel AD susceptibility loci. Interestingly the associated genes at several of these loci implicate the immune system in late-onset AD, specifically the innate immune system. Many recent lines of evidence suggest that the immune system plays a key role in AD initiation and progression, but the actual mechanistic dysfunction of the immune system in this neurodegenerative disease remains unknown. Genetic studies and pathology hint that the immune system’s ability to mount a productive response has been lost in AD with detrimental consequences. Post-mortem pathology of individuals with AD reveals an infiltration of T cells in the hippocampus, a region expected to be immune privileged, leading to speculation that AD might have an infectious component to its etiology or progression. In parallel, the pathogen hypothesis has garnered more support for a possible pathogenic etiology of AD. We propose to leverage our understanding of the immune system to determine if the immune response to the neuroinvasive pathogen human simplex virus (HSV)-1 is modulated by AD genetic associations, leading to increased risk for AD. We will take a comprehensive approach using cutting-edge tools to explore this hypothesis in AD. Combining genetics, human immunology, transcriptomics, virology, in vitro models, computational biology and epidemiology, we will dissect the interaction between HSV-1 infections and AD genetics. For this application, we propose a multifaceted approach using cutting-edge technology to: 1) identify the microglia response to HSV-1 infection based on each individual’s genetic background; 2) examine how these microglia function as antigen-presenting cells to T cells, a key cell type in resolving active infections; and 3) determine the interaction of HSV-1 and AD genetics in two well-establish cohorts and one anti-viral clinical trial in AD.