Human Herpesvirus 6B in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome pathogenesis: temporal analysis of viral reactivation and immunity to elucidate cause vs effect

项目摘要/摘要 我们的研究项目《人类疱疹病毒6B与肌痛性脑脊髓炎/慢性疲劳综合征》 发病机制：病毒重新激活和免疫的时间分析，以阐明原因与结果“，旨在验证 或者驳斥我们关于人类疱疹病毒对症状严重程度的作用的初步研究结果 在ME/CFS中，并确定病毒重新激活是免疫失调的原因还是结果。 我们将跟踪更多的同意个人(n=306)，使用我们设计的严格方案来 招募英国ME/CFS生物库(UKMEB)的参与者。我们同意重新联系UKMEB的参与者 ME/CFS(包括那些患有严重疾病的患者)和非疾病对照组(n=500)，临床 评估和收集生物样本(血液和唾液)。我们还将招募另一个对照小组， 由出现典型ME/CFS症状的长期COVID患者(n=30)以及 未出现急性发病后新冠肺炎远期急性后遗症(简称冠心病组)30例。这个 研究人群将包括18-60岁，有ME/CFS或Long诊断的个人 符合纳入标准的COVID与ME/CFS，以及健康对照和COVID较短的人 和排除标准。 我们将对ME/CFS患者进行纵向分析，以确定其相关性和时间性 HHV-6B DNA浓度与ME/CFS症状严重程度及唾液病毒DNA检测的关系 每月一次，连续6个月，同时进行症状评分。以确认唾液中HHV-6B DNA的增加反映了 全身复活后，我们将检测血液中病毒的RNA、DNA和蛋白质，并假设唾液RNA 将与唾液DNA浓度相关，当ME/CFS症状出现时，所有这些都将一起增加 抬高了。我们还将测量HHV-6B反应性CD4+和CD8+T细胞的频率、表型和功能 在患有ME/CFS的人身上。应用流式细胞术，并将研究HHV-6B对人肝癌细胞的免疫抑制作用 用基因表达分析法研究ME/CFs中巨噬细胞的抗原提呈。我们假设HHV- 6B特异性T细胞随着ME/CFS症状的恶化而扩张，但对HHV-6B控制无效，我们将 测试在符合诊断标准的人中，是否观察到长冠状病毒感染的人也有类似的变化 对于ME/CFS。 我们的目标源于我们成功的初步研究，目的是确定HHV-6B重新激活是否与 ME/CFS发病机制，并产生生物学证据，为有针对性的干预提供信息，如 疫苗研发。

PROJECT SUMMARY / ABSTRACT Our research project, entitled “Human Herpesvirus 6B in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome pathogenesis: temporal analysis of viral reactivation and immunity to elucidate cause vs effect”, aims to validate or refute the findings of our preliminary study on the role of human herpesviruses on the severity of symptoms in ME/CFS, and to determine if the virus reactivation is a cause or a consequence of the immune dysregulation. We will follow-up a larger number of consenting individuals (n=306), using our rigorous protocols designed to recruit participants to the UK ME/CFS Biobank (UKMEB). We have consent to re-contact UKMEB participants with ME/CFS (including those with a severe form of disease), and non-diseased controls (n=>500), with clinical assessments and collection of biosamples (blood and saliva). We will also recruit another comparison group, consisting of people with Long-COVID presenting with symptoms typical of ME/CFS (n=30), as well as people who did not develop long-term post-acute sequelae of COVID-19 after acute illness (Short COVID: n=30). The study population will comprise individuals from 18 - 60 years old, who have a diagnosis for ME/CFS or Long COVID with ME/CFS, as well as healthy controls and people who had Short COVID, in compliance with inclusion and exclusion criteria. We will perform a longitudinal analysis of people living with ME/CFS to determine the association and temporal relationship between HHV-6B DNA concentration and ME/CFS symptom severity, measuring viral DNA in saliva monthly for 6 months, alongside symptom scoring. To confirm that increases in HHV-6B DNA in saliva reflect systemic reactivation, we will measure blood viral RNA, DNA and protein, with the hypothesis that saliva RNA will correlate with saliva DNA concentration, and that all will increase together when ME/CFS symptoms are elevated. We will also measure frequency, phenotype and function of HHV-6B-reactive CD4+ and CD8+ T cells in people with ME/CFS. using flow cytometry, and will investigate the immunosuppressive effects of HHV-6B on antigen presentation in macrophages in ME/CFS using gene expression analysis. We hypothesize that HHV- 6B-specific T cells expand as ME/CFS symptoms worsen but are ineffective in for HHV-6B control, and we will test whether similar changes are observed in those with Long COVID in people who fulfill the diagnostic criteria for ME/CFS. Our goal, which stems from our successful pilot study, is to establish whether HHV-6B reactivation is causal in ME/CFS pathogenesis, and generate biological evidence which will inform targeted interventions such as vaccine development.