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

长期以来，人们一直怀疑病毒感染在肌萎缩侧索硬化症中的潜在作用，但仍不确定。众多常见的 病毒是嗜神经性的，可导致神经系统疾病，包括脑炎、脑膜炎和急性 迟缓性瘫痪，但证明ALS患者存在病毒感染的尝试给出了不一致的结论 结果。最近的实验工作表明，病毒感染可能会扰乱正常的分布和 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在细胞质中的分离及其裂解成两个片段，其中一个倾向于聚集 对TDP43功能有显性负向影响。胞质TDP43包涵体的形成是一种 散发性肌萎缩侧索硬化症以及许多额颞叶痴呆的病理特征是一致的。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，这种病毒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 神经细胞和神经胶质细胞的感染也可能导致ALS的病理。因此，我们建议进行一项 重复采集血样中人病毒(&gt；400种和株)的探索性研究 在肌萎缩侧索硬化症首发症状出现前几年。我们将使用最近开发的噬菌体展示文库 表达来自所有脊椎动物和虫媒病毒的481,966个重叠多肽(VirScan)。通过探索 多年后患上ALS的健康年轻人的病毒体，我们可以识别出 与增加的风险相关。此外，我们还将测量血清中神经丝轻链的浓度 神经退行性变的敏感标志物(NFL)研究病毒感染与NFL的关系 立面。这种独特的研究是由武装部队健康维护的数据库实现的 监察处和国防部血清部存档的6000多万份血清样本 存储库。这些样本是从1100多万名年轻男女中收集的，他们在 美国陆军、海军、海军陆战队和空军用于艾滋病毒感染筛查。每个人都在 从进入现役时开始，平均每两年抽样一次。通过对病毒进行剖析， 重复采样，就有可能识别出患有ALS和 将这一模式与年龄、性别和种族相匹配的保持健康的对照组进行比较。基于 我们的初步工作，我们希望能够通过可用的血清样本识别150多例ALS病例 进行拟议中的调查。我们团队一直在国防部的基础上进行研究 血清库已有超过15年的历史，因此与军事机构在这方面的合作有很长的历史 目的。这项研究将与统一服务大学的调查人员合作进行 健康科学和马萨诸塞州综合医院ALS诊断和护理的专业医生 医院。

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.