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

基本信息

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
项目类别：
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

项目摘要

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.

概括感染 SARS-CoV-2 后，很大一部分人会出现持续症状或健康状况并发症，通常称为“长期新冠肺炎”或新冠肺炎 (COVID-19) 急性后遗症 (PASC) 宿主、病毒。影响PASC发展的环境因素尚不清楚，阻碍了发展 PASC 也没有生物标志物，这使得 PASC 的开发变得复杂。在拟议的工作中，我们将基于显示免疫和代谢的初步数据。我们收集了与 PASC 特定症状相关的跨学科研究。协作团队在 SARS-CoV-2 病毒学、病毒免疫、RNA 病毒持久性、切割方面拥有全球专业知识基于边缘组织的病毒检测、COVID-19 动物模型、队列方法、传染病诊断、高维单细胞数据分析以及呼吸道病毒感染的性别差异。我们的团队包括 NIH 资助的 COVID-19 血清学卓越中心的主要研究人员和四项大型 COVID-19 临床研究，招募了超过 1500 名参与者，并进行了纵向血液和呼吸系统研究从症状出现后 2 天到症状出现后 18 个月进行粘膜取样和症状调查我们将研究持久性病毒抗原或 RNA、宿主免疫反应、性别、我们的中心假设是，独特且持续的免疫代谢特征是。在目标 1 中，我们将使用免疫代谢高维流。细胞计数、靶向代谢基因表达谱和功能测定以及单细胞 RNA 测序剖析驱动这些独特群体分化和功能的代谢和免疫程序具有明显 PASC 症状和后遗症的个体以及具有完全症状的个体的纵向样本在目标 2 中，我们将确定 PASC 的具体症状和后遗症是否已康复。与 SARS-CoV-2 特异性 B 和 T 细胞反应的长期进化相关，提示病毒抗原或 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-2 RNA 或抗原在多个器官中持续存在的性别差异，这可能导致与组织中的免疫代谢失调有关，并与小鼠 PASC 的行为迹象相关。通过本提案中概述的实验，我们将解决某种形式的 SARS-CoV-2 是否持续存在有助于 PASC，或者如果 PASC 完全是远程病毒感染的结果，则问题巨大的临床意义。