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.

项目摘要 /摘要 我们的研究项目，名为“肌力脑脊髓炎 /慢性疲劳综合征的人类疱疹病毒6B 发病机理：病毒重新激活和免疫力的暂时分析以阐明导致效应”，旨在验证 或驳斥我们关于人疱疹病毒在符号严重程度的作用的初步研究的结果 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。 我们将使用旨在 招募参与者到英国ME/CFS Biobank（UKMeb）。我们同意重新接触UKMEB参与者 使用ME/CFS（包括具有严重疾病形式的患者）和非疾病的对照（n => 500），并带有临床 评估和收集生物样本（血液和唾液）。我们还将招募另一个比较小组 由长期浮动的人组成的人/CFS的症状（n = 30）以及人 谁没有在急性疾病后发生长期急性后的急性后遗症（短期：n = 30）。这 研究人群将完成18至60岁的个人，他们对我/CFS有诊断或长时间的诊断 符合包容性 和排除标准。 我们将对与我/CF一起生活的人进行纵向分析，以确定关联和临时性 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 每月持续6个月，以及症状评分。确认唾液中HHV-6B DNA的增加反映 系统性重新激活，我们将用唾液RNA的假设来测量血液病毒RNA，DNA和蛋白 将与唾液DNA浓度相关，并且当me/cfs符号为 高架。我们还将测量HHV-6B反应CD4+和CD8+ T细胞的频率，表型和功能 在我/CFS的人中。使用流式细胞仪，并将研究HHV-6B对HHV-6B的免疫抑制作用 使用基因表达分析，在ME/CFS中巨噬细胞中的抗原表现。我们假设HHV- 6b特异性的T细胞随着ME/CFS符号未知而扩展，但对HHV-6B对照无效，我们将 测试在符合诊断标准的人中是否观察到类似的变化 对我/CFS。 我们成功的试点研究中的植物是我们的目标是确定HHV-6B重新激活是否是因果关系 ME/CFS发病机理，并生成生物学证据，这些证据将告知有针对性的干预措施，例如 疫苗开发。