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ALS中的潜在作用，但仍不确定。许多常见 病毒是嗜神经性的，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， 结果最近的实验工作表明，病毒感染可能会破坏正态分布， RNA结合蛋白的代谢，包括TDP43。例如，感染柯萨奇B3病毒会导致 TDP43在细胞质中分离并裂解成两个片段，其中一个倾向于聚集 并且对TDP43功能具有显性负效应。细胞质TDP43包涵体的形成是一个重要的因素。 在散发性ALS中以及在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触发TDP43的破坏和聚集过程， 即使在没有病毒的情况下，它也可以在细胞间传播。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有助于ALS病理学。因此，我们建议进行一项 在重复采集的血液样本中对整个人类病毒组（> 400种和菌株）进行探索性研究 在ALS的第一个症状出现前几年。我们将使用最近开发的噬菌体展示库 表达481，966个源自所有脊椎动物和虫媒病毒的重叠肽（VirScan）。通过探索 健康年轻人的病毒组在多年后发展为ALS，我们可以识别出 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)，神经退行性变的敏感标志物，以研究病毒感染与NfL之间的关系 海拔这样一个独特的研究是可能的数据库维护的武装部队卫生 监控分支和超过6000万份血清样本存档在国防部血清 仓库。这些样本是从1100多万在美国服役的年轻男女中收集的。 美国陆军、海军、海军陆战队和空军用于筛查HIV感染。每个人都对 从开始服役时起每两年进行一次抽样调查。通过分析病毒组， 重复的样本，有可能确定过去和新的感染的个人谁发展ALS和 将这一模式与年龄、性别和种族相匹配的健康对照组进行比较。基于 我们的初步工作，我们预计能够确定超过150事件ALS病例与可用的血清样本 进行拟议中的调查我们的团队一直在进行研究， 血清储存库超过15年，因此与军事机构合作的历史很长。 目的.这项研究将与美国陆军大学的研究人员合作进行， 在马萨诸塞州总医院， 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.