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: 10117845
• 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/10117845
• 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，但仍然不确定。许多常见 病毒是神经性的，可能引起神经系统疾病，包括脑炎，脑膜炎和急性 松弛的瘫痪，但试图证明ALS患者的病毒感染已有不一致 结果。最近的实验工作表明，病毒感染可能会破坏正态分布和 RNA结合蛋白的代谢，包括TDP43。例如，感染Coxsackievivirus B3原因 TDP43在细胞质中的分离及其裂解成两个片段，其中一个倾向于聚集 并对TDP43功能具有显着的负面影响。细胞质TDP43夹杂物的形成是 零星ALS以及许多额颞痴呆症的病理特征一致。它有 因此，假设病毒感染可以触发TDP43的破坏和聚集过程 即使在没有病毒的情况下，也可以从细胞传播到细胞。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，我们建议进行 在收集的重复血液样本中对整个人类病毒蛋白（> 400种和菌株）的探索性研究 在ALS首次症状发作之前的几年。我们将使用最近开发的噬菌体显示库 表达481,966个重叠的肽重叠，这些肽来自所有脊椎动物和刺病毒（VirScan）。通过探索 多年后发展ALS的健康年轻人的病毒素，我们可以识别出病毒感染 与风险增加有关。此外，我们将测量神经丝轻链的血清浓度 （NFL），一种神经变性的敏感标记，研究病毒感染与NFL之间的关系 海拔。武装部队健康维护的数据库使得如此独特的研究成为可能 监视分支和国防部血清存档的超过6000万血清样品 存储库。这些样本是从超过1100万的年轻男女中收集的 美国陆军，海军，海军陆战队和空军筛查艾滋病毒感染。每个人都为 平均每两年开始一次样本开始现役。通过在 重复样本，可以识别出发展ALS和的个人的过去和新感染 将这种模式与保持健康的年龄，性别和种族相匹配的控制模式进行比较。基于 我们的初步工作，我们希望能够识别出150多个可用血清样品的事件ALS病例 拟议的调查。我们的团队一直在根据国防部进行研究 血清存储库已有15年以上，因此与军事机构合作的历史悠久 目的。这项研究将与制服服务大学的调查员合作进行 健康科学以及马萨诸塞州一般从事ALS诊断和护理的医生 医院。