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.

概括 SARS-COV-2感染后，很大一部分人会出现持续的症状或健康 并发症，通常称为Covid-19（PASC）的“长covid”或急性后遗症。宿主，病毒 影响PASC发展的环境因素尚不清楚，这阻碍了发展 理论的患者。 PASC也没有生物标志物，这使得 诊断。在拟议的工作中，我们将基于显示免疫和代谢的初步数据 失调与PASC的特定症状相关。我们已经组装了一个跨学科 与SARS-COV-2病毒学，病毒免疫学，RNA病毒持久性，切割方面的全球专业知识的合作团队 基于边缘组织的病毒测定，COVID-19的动物模型，队列方法论，传染病 诊断，高维单细胞数据分析以及呼吸病毒感染的基于性别的差异。 我们的团队包括由NIH资助的Covid-19血清学卓越中心和 四项大型COVID-19，> 1500名参与者和纵向血液和呼吸道的临床研究 粘膜取样以及症状调查从症状发作后2天到18个月后 症状发作。我们将研究持续性病毒抗原或RNA的交集，宿主免疫反应，性别，性别 肥胖和pasc。我们的中心假设是，明显和持续的免疫代谢概况是 与特定的杂化后条件相关。在AIM 1中，我们将使用免疫代谢高维流量 细胞仪，靶向代谢基因表达分析和功能测定以及单细胞RNA测序 剖析推动这些独特人群的分化和功能的代谢和免疫程序 在具有不同PASC符号和后遗症的个体的纵向样本中 从Covid-19恢复。在AIM 2中，我们将确定PASC的特定症状和后遗症是否 与SARS-COV-2特异性B和T细胞反应的长时间演变有关的病毒抗原 或RNA持久性并由肥胖制备。在AIM 3中，我们将使用SARS-COV-2的新型鼠标模型 评估多个器官中SARS-COV-2 RNA或抗原持续性的性别差异，这可能导致 在组织中的免疫代谢失调，并与小鼠PASC的行为迹象相关。通过 该提案中概述的实验，我们将解决某种形式的SARS-COV-2持久性 有助于PASC或PASC完全是远程病毒感染的结果，这是一个问题 巨大的临床意义。