Intersection of HSV-1 and microglial genetics in AD

项目概要 阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是进行性认知障碍 衰退和痴呆。全基因组关联研究已经确定了新的 AD 易感位点。有趣的是 其中几个位点的相关基因与迟发性 AD 的免疫系统有关，特别是 先天免疫系统。最近的许多证据表明，免疫系统在 AD 中发挥着关键作用 启动和进展，但免疫系统的实际机制功能障碍在此 神经退行性疾病仍然未知。遗传学研究和病理学表明，免疫系统 AD 患者失去了做出有效反应的能力，并产生了有害的后果。尸检 AD 患者的病理学揭示了海马体中 T 细胞的浸润，该区域预计会 免疫特权，导致人们猜测 AD 的病因可能具有感染性成分，或者 进展。与此同时，病原体假说为可能的致病病因学获得了更多支持 公元。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 增加患 AD 的风险。我们将使用尖端工具采取全面的方法来探索这个问题 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 感染与 AD 之间的相互作用 遗传学。对于此应用，我们提出了一种使用尖端技术的多方面方法：1) 识别 基于每个个体的遗传背景，小胶质细胞对 HSV-1 感染的反应； 2）检查这些 小胶质细胞充当 T 细胞的抗原呈递细胞，T 细胞是解决活动性感染的关键细胞类型；和 3) 在两个完善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 在公元。

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.