Sex, obesity, immunometabolism, and viral persistence in post-acute sequelae of SARS-CoV-2 infection

SARS-CoV-2 感染急性后遗症中的性别、肥胖、免疫代谢和病毒持续性

• 批准号: 10554731
• 负责人: ANDREA L COX
• 金额: $ 120.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554731
• 关键词: 2019-nCoV; Address; Affect; Animal Model; Animals; Antibodies; Antigens; Autoantibodies; Automobile Driving; B-Lymphocytes; Behavioral; Biological Assay; Biological Markers; Biotechnology; Blood; Blood Cells; COVID-19; Cells; Chronic; Clinical; Clinical Data; Clinical Research; Clonality; Cohort Studies; Communicable Diseases; Complement; Coupled; Data; Data Analyses; Development; Diagnostic; Enrollment; Environmental Risk Factor; Evolution; Fatigue; Female; Flow Cytometry; Funding; Gene Expression; Gene Expression Profiling; Health; Heterogeneity; Human; Immune; Immune response; Immunity; Immunization; Individual; Inflammation; Knowledge; Lead; Link; Long COVID; Measures; Metabolic; Metabolic Pathway; Methodology; Mus; Non obese; Obesity; Organ; Participant; Patients; Persons; Phenotype; Population; Post-Acute Sequelae of SARS-CoV-2 Infection; Proteins; Quality of life; RNA; RNA Viruses; Recovery; Research Personnel; Resolution; Respiratory Mucosa; Respiratory System; SARS-CoV-2 antigen; SARS-CoV-2 infection; Sampling; Serology; Sex Differences; Site; Suggestion; Surface; Surveys; Symptoms; T cell response; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Tissues; United Kingdom; United States National Institutes of Health; Viral; Viral Antigens; Viral Respiratory Tract Infection; Virus; Virus Diseases; Work; acute symptom; base; biological sex; cohort; design; disease diagnostic; exhaustion; experience; experimental study; follow-up; high dimensionality; innovation; male; metabolic profile; mouse model; novel; peripheral blood; persistent symptom; post SARS-CoV-2 infection; post-COVID conditions; programs; respiratory virus; response; sex; single cell analysis; single-cell RNA sequencing; theories; therapeutic development; viral RNA; virology

Summary After SARS-CoV-2 infection, a significant percentage of people develop persistent symptoms or health complications, often referred to as ‘long COVID’ or post-acute sequelae of COVID-19 (PASC). The host, virus and environmental factors affecting the development of PASC are not well known, which hinders development of therapeutics for patients. There also are no biomarkers for PASC, which complicates development of diagnostics. In the proposed work, we will build on preliminary data showing immune and metabolic dysregulation correlating with specific symptoms of PASC. We have assembled a cross-disciplinary collaborative team with global expertise in SARS-CoV-2 virology, viral immunity, RNA virus persistence, cutting edge tissue-based viral assays, animal models of COVID-19, cohort methodology, infectious diseases diagnostics, high-dimensional single cell data analysis, and sex-based differences in respiratory viral infection. Our team includes the primary investigators of an NIH-funded COVID-19 Serology Center of Excellence and four large COVID-19 clinical studies with > 1500 enrolled participants and longitudinal blood and respiratory mucosal sampling coupled with symptom surveys from 2 days after symptom onset through 18 months after symptom onset. We will study the intersection of persistent viral antigen or RNA, host immune response, sex, obesity, and PASC. Our central hypothesis is that distinct and persistent immune metabolic profiles are associated with specific post-COVID conditions. In Aim 1, we will use immune-metabolic high-dimensional flow cytometry, targeted metabolic gene expression profiling and functional assays, and single cell RNA sequencing to dissect the metabolic and immune programs driving differentiation and function of these unique populations in longitudinal samples from individuals with distinct PASC symptoms and sequelae and those with complete recovery from COVID-19. In Aim 2, we will determine whether specific symptoms and sequelae of PASC are associated with prolonged evolution of SARS-CoV-2-specific B and T cell responses suggestive of viral antigen or RNA persistence and facilitated by obesity. In Aim 3, we will use our novel mouse model of SARS-CoV-2 to evaluate sex differences in the persistence of SARS-CoV-2 RNA or antigen in multiple organs, which may lead to immune-metabolic dysregulation in tissues and correlate with behavioral signs of PASC in mice. Through the experiments outlined in this proposal, we will address whether some form of SARS-CoV-2 persistence contributes to PASC or if PASC is entirely a consequence of a remote virus infection, a question with enormous clinical implications.

摘要 在感染SARS-CoV-2后，相当大比例的人出现持续的症状或健康 并发症，通常被称为“慢性冠状病毒病”或新冠肺炎的急性后遗症(PASC)。宿主、病毒 影响PASC发展的环境因素还不是很清楚，阻碍了发展 为病人提供的治疗方法。PASC也没有生物标志物，这使得PASC的发展复杂化 诊断。在拟议的工作中，我们将以初步数据为基础，显示免疫和新陈代谢 与PASC的特定症状相关的调节失调。我们已经组建了一个跨学科的 在SARS-CoV-2病毒学、病毒免疫、RNA病毒持久性、切割等领域拥有全球专业知识的协作团队 边缘组织病毒检测、新冠肺炎动物模型、队列方法学、传染病 呼吸道病毒感染的诊断、高维单细胞数据分析和基于性别的差异。 我们的团队包括美国国立卫生研究院资助的新冠肺炎血清学卓越中心的主要调查人员和 四项大型新冠肺炎临床研究，参与者为1500人，纵向血液和呼吸系统 从症状出现后2天到18个月的粘膜取样和症状调查 症状出现。我们将研究持久性病毒抗原或RNA、宿主免疫反应、性别、 肥胖和PASC。我们的中心假设是不同的和持久的免疫代谢特征 与特定的冠状病毒感染后情况有关。在目标1中，我们将使用免疫代谢高维流动 细胞学、靶向代谢基因表达谱和功能分析以及单细胞RNA测序 剖析驱动这些独特种群分化和功能的代谢和免疫程序 在有明显PASC症状和后遗症的个体以及完全 从新冠肺炎中恢复过来。在目标2中，我们将确定PASC的特定症状和后遗症是否 与病毒抗原提示的SARS-CoV-2特异性B和T细胞应答的长期进化有关 或RNA持久性，并由肥胖促进。在目标3中，我们将使用我们的新型SARS-CoV-2小鼠模型来 评估SARS-CoV-2RNA或抗原在多个器官中持续存在的性别差异，这可能会导致 与组织免疫代谢紊乱有关，并与PASC的行为体征相关。穿过 在这份提案中概述的实验中，我们将解决是否存在某种形式的SARS-CoV-2 导致PASC，或者如果PASC完全是远程病毒感染的结果， 具有巨大的临床意义。