Intersection of HSV-1 and microglial genetics in AD

项目摘要 阿尔茨海默病(AD)是一种以进行性认知为特征的与年龄相关的神经退行性疾病 衰老和痴呆症。全基因组关联研究已经确定了新的AD易感基因。有趣的是 其中几个基因座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，免疫系统在阿尔茨海默病中起着关键作用 启动和进展，但在这个过程中免疫系统的实际机械性功能障碍 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 在AD中失去了做出有效反应的能力，造成了有害的后果。验尸报告 阿尔茨海默病患者的病理显示，海马区有T细胞的渗透，预计这一区域 免疫特权，导致猜测AD的病因可能有传染性成分或 进步。同时，病原体假说也为可能的病原学获得了更多的支持。 公元一代的。我们建议利用我们对免疫系统的了解来确定免疫反应 对于神经侵袭性病原体，人类单纯疱疹病毒(HSV)-1受到AD遗传关联的调节，导致 增加AD的风险。我们将使用尖端工具采取全面的方法来探索这一点 AD中的假设。结合遗传学，人类免疫学，转录学，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。对于这一应用，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的小胶质细胞对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；以及3) 在两个已建立的队列和一个抗病毒临床试验中确定HSV-1和AD遗传学的相互作用 在公元后。

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.