Serological profiling of the human virome and ALS risk in a military population

军人人群中人类病毒组和 ALS 风险的血清学分析

• 批准号: 10252746
• 负责人: ALBERTO ASCHERIO
• 金额: $ 50万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252746
• 关键词: Serological; profiling; human; virome; ALS

A potential role of viral infections in ALS has long been suspected, but it remains uncertain. Numerous common viruses are neurotropic and can cause neurological diseases, including encephalitis, meningitis, and acute flaccid paralysis, but attempts to demonstrate viral infections in individuals with ALS have given inconsistent results. Recent experimental work has demonstrated that viral infections may disrupt the normal distribution and metabolism of RNA binding proteins, including TDP43. For example, infection with Coxsackievirus B3 causes segregation of TDP43 in the cytoplasm and its cleavage into two fragments, one of which tends to aggregate and has a dominant negative effect on TDP43 function. The formation of cytoplasmic TDP43 inclusions is a consistent pathological feature in sporadic ALS, as well as in many cases of frontotemporal dementia. It has therefore been hypothesized that viral infections can trigger a process of disruption and aggregation of TDP43, which could then propagate from cell to cell, even in the absence of the virus. Numerous other effects of viral infection on neuronal and glial cells could also contribute to ALS pathology. We propose therefore to conduct an exploratory study of the entire human virome (> 400 species and strains) in repeated blood samples collected years before the onset of the first symptoms of ALS. We will use a recently developed phage display library expressing 481,966 overlapping peptides derived from all vertebrate and arboviruses (VirScan). By exploring the virome of healthy young adults who years later developed ALS, we can identify viral infections that are associated with an increased risk. Further, we will measure serum concentrations of neurofilament light chain (NfL), a sensitive marker of neurodegeneration to investigate the relation between viral infections and NfL elevations. Such a unique study is made possible by the databases maintained by the Armed Forces Health Surveillance Branch and the over 60 million serum samples archived in the Department of Defense Serum Repository. These samples have been collected from over 11 million young men and women who served in the US Army, Navy, Marines, and Air Force for screening for HIV infection. Each individual has contributed on average with a sample every two years starting at the time of entry into active duty. By profiling the virome in repeated samples, it is possible to identify past and new infections in individuals who developed ALS and compare this pattern with that of controls matched by age, sex, and ethnicity who remained healthy. Based on our preliminary work, we expect to be able to identify over 150 incident ALS cases with available serum samples for the proposed investigation. Our team has been conducting research based on the Department of Defense Serum Repository for over 15 years and has thus a long history of collaboration with military institutions for this purpose. This study will be conducted in collaboration with investigators at the Uniformed Services University for the Health Sciences and with a physician specialized in ALS diagnosis and care at the Massachusetts General Hospital.

长期以来人们一直怀疑病毒感染在 ALS 中的潜在作用，但仍不确定。众多常见的 病毒具有嗜神经性，可引起神经系统疾病，包括脑炎、脑膜炎和急性 弛缓性麻痹，但试图证明 ALS 患者的病毒感染结果不一致 结果。最近的实验工作表明，病毒感染可能会破坏正常分布并 RNA 结合蛋白的代谢，包括 TDP43。例如，感染柯萨奇病毒 B3 会导致 TDP43 在细胞质中分离并分裂成两个片段，其中一个倾向于聚集 并且对 TDP43 功能具有显着的负面影响。细胞质 TDP43 包涵体的形成是 散发性 ALS 以及许多额颞叶痴呆病例中具有一致的病理特征。它有 因此假设病毒感染可以引发 TDP43 的破坏和聚集过程， 即使没有病毒，它也可以从一个细胞传播到另一个细胞。病毒的许多其他影响 神经元和神经胶质细胞的感染也可能导致 ALS 病理学。因此，我们建议开展一次 对重复采集的血液样本中的整个人类病毒组（> 400 个物种和菌株）进行探索性研究 ALS 首次症状出现前数年。我们将使用最近开发的噬菌体展示库 表达源自所有脊椎动物和虫媒病毒的 481,966 个重叠肽 (VirScan)。通过探索 通过研究多年后患上 ALS 的健康年轻人的病毒组，我们可以识别出以下病毒感染： 与风险增加相关。此外，我们将测量神经丝轻链的血清浓度 (NfL)，神经退行性变的敏感标记，用于研究病毒感染与 NfL 之间的关系 海拔。武装部队卫生部门维护的数据库使这种独特的研究成为可能 监测部门和国防部血清库中存档的超过 6000 万份血清样本 存储库。这些样本是从超过 1100 万在军队服役的年轻男女中采集的。 美国陆军、海军、海军陆战队和空军用于艾滋病毒感染筛查。每个人都做出了贡献 从进入现役时开始，平均每两年进行一次抽样。通过分析病毒组 通过重复样本，可以识别患有 ALS 的个体过去和新的感染 将此模式与年龄、性别和种族相匹配且保持健康的对照组的模式进行比较。基于 在我们的初步工作中，我们预计能够利用可用的血清样本识别超过 150 例 ALS 病例 对于拟议的调查。我们的团队一直在以国防部为基础进行研究 血清库已有 15 年以上的历史，因此与军事机构在这方面有着悠久的合作历史 目的。这项研究将与军警大学的研究人员合作进行 健康科学以及马萨诸塞州总医院专门从事 ALS 诊断和护理的医生 医院。