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

肌痛性脑脊髓炎/慢性疲劳综合症发病机制中的人类疱疹病毒 6B：病毒再激活和免疫的时间分析，以阐明因果关系

• 批准号: 10502327
• 负责人: Jackie Cliff
• 金额: $ 53.17万
• 依托单位: LONDON SCH/HYGIENE & TROPICAL MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502327
• 关键词: 2019-nCoV; Acute; Adult; Affect; Antigen Presentation; Antigen-Presenting Cells; Bacterial Infections; Biological; Biological Assay; Blood; Blood specimen; CD8-Positive T-Lymphocytes; COVID-19; Cell physiology; Cells; Characteristics; Chemical Exposure; Chronic Fatigue Syndrome; Clinical; Clinical assessments; Collection; Consent; Cryopreservation; DNA; Data; Data Collection; Development; Diagnosis; Diagnostic tests; Disease; Endocrine; Enrollment; Etiology; Event; Evidence based treatment; Exclusion Criteria; Exertion; Family member; Fatigue; Flow Cytometry; Frequencies; Funding; Gene Expression Profiling; Goals; HHV-6B; Herpesviridae; Human; Immune; Immune response; Immunity; Immunologic Surveillance; Immunologics; Immunosuppression; Individual; Infection; Interferon Type II; Interleukin-2; Intervention; Knowledge; Laboratories; Life; Long COVID; Measures; Multiple Sclerosis; Mycoses; Nature; Outcome; Participant; Pathogenesis; Patient Recruitments; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Pilot Projects; Post-Acute Sequelae of SARS-CoV-2 Infection; Prognostic Marker; Proteins; Protocols documentation; RNA; Recurrence; Relapse; Research Project Grants; Role; Saliva; Salivary; Severities; Severity of illness; Stress; Symptoms; Syndrome; System; T cell response; T-Lymphocyte; TNF gene; Testing; Time; United States National Institutes of Health; Viral; Viral Markers; Viral Proteins; Virus; Virus Diseases; Work; antigen-specific T cells; base; biobank; clinical phenotype; cohort; comparison group; coronavirus disease; design; diagnostic criteria; digital; epidemiology study; follow-up; inclusion criteria; latent infection; longitudinal analysis; macrophage; monocyte; post SARS-CoV-2 infection; recruit; relating to nervous system; saliva sample; sample collection; stem; stressor; study population; vaccine development; vaccine immunotherapy; viral DNA; viral RNA

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.

项目概要/摘要 我们的研究项目，题为“肌痛性脑脊髓炎/慢性疲劳综合症中的人类疱疹病毒 6B” 发病机制：病毒再激活和免疫的时间分析，以阐明因果关系”，旨在验证 或反驳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。 我们将使用我们旨在跟踪更多同意个人（n = 306）的严格协议来跟踪 招募参与者到英国 ME/CFS 生物库 (UKMEB) 我们同意重新联系 UKMEB 参与者。 患有 ME/CFS（包括患有严重疾病的患者）和非疾病对照 (n=>500)，具有临床 我们还将招募另一个对照组，进行评估和收集生物样本（血液和唾液）。 包括表现出 ME/CFS 典型症状的长期新冠肺炎患者 (n=30)，以及 急性病后没有出现长期的 COVID-19 急性后遗症的人（简称 COVID：n=30）。 研究人群将包括 18 至 60 岁、诊断为 ME/CFS 或 Long 的个体 患有 ME/CFS 的新冠肺炎患者，以及健康对照者和患有短期新冠肺炎的人，符合包容性 和排除标准。 我们将对 ME/CFS 患者进行纵向分析，以确定关联性和时间性 HHV-6B DNA 浓度与 ME/CFS 症状严重程度之间的关系，测量唾液中的病毒 DNA 每月一次，持续 6 个月，同时进行症状评分，以确认唾液中 HHV-6B DNA 的增加有所反映。 全身重新激活，我们将测量血液病毒 RNA、DNA 和蛋白质，假设唾液 RNA 与唾液 DNA 浓度相关，当 ME/CFS 症状出现时，所有这些都会一起增加 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。 使用流式细胞术对 ME/CFS 患者进行研究，并将研究 HHV-6B 对 ME/CFS 患者的免疫抑制作用。 我们使用基因表达分析捕获了 ME/CFS 巨噬细胞中的抗原呈递。 6B 特异性 T 细胞随着 ME/CFS 症状恶化而扩增，但对 HHV-6B 控制无效，我们将 测试在符合诊断标准的长期新冠肺炎患者中是否观察到类似的变化 对于 ME/CFS。 我们的目标源于我们成功的试点研究，即确定 HHV-6B 重新激活是否与 ME/CFS 发病机制，并生成生物学证据，为有针对性的干预措施提供信息，例如 疫苗开发。