Tissue and organ specific human B cell immunity: Supplement - Metabolic Risk Factors and Inflammation in PASC Development

组织和器官特异性人类 B 细胞免疫：补充 - PASC 发育中的代谢危险因素和炎症

• 批准号: 10554879
• 负责人: Nathaniel Bernard Erdmann
• 金额: $ 103.33万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554879
• 关键词: 2019-nCoV; Acute; Acute respiratory infection; Adipose tissue; Affect; B-Lymphocytes; Biological; Blood Banks; Blood specimen; COVID-19 diagnosis; COVID-19 patient; Chronic; Clinic; Computerized Medical Record; Consent; Coronavirus; Data; Deep South; Development; Diabetes Mellitus; Diagnosis; Exhibits; Functional disorder; Future; Goals; Health; Human; Immune; Immune response; Immunity; Immunologic Factors; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Information Systems; Intervention; Link; Long COVID; Long-Term Effects; Metabolic; Metabolic Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Participant; Patients; Persons; Population; Post-Acute Sequelae of SARS-CoV-2 Infection; Questionnaires; Respiratory System; Risk; Risk Factors; SARS-CoV-2 infection; Sampling; Symptoms; Syndrome; T-Lymphocyte; Testing; Time; Tissues; Viral; Viral Antigens; Viral reservoir; Virus; acute infection; body system; cardiometabolism; cohort; comorbidity; disabling symptom; immune activation; improved; insight; response

Although coronaviruses are typically believed to cause acute respiratory infections, emerging evidence suggests that viral antigen or perhaps even intact virus may be found outside of the respiratory system for extended periods of time following acute infection. Moreover, the data show that numerous non-respiratory tract tissues, including adipose tissue, can serve as a reservoir for the virus, suggesting that this infection may have long-term effects on multiple organ systems of the body. It is now recognized that a significant fraction of individuals diagnosed with COVID-19 will continue to exhibit a wide array of debilitating symptoms, collectively referred to as Post-Acute Sequalae of SARS-CoV-2 (PASC or Long-COVID), for weeks to months after infection. Given the enormous number of SARS-CoV-2 infected individuals who are likely to develop PASC, there is a critical need to better understand the risk factors associated with the different PASC manifestations and to develop appropriate interventions to treat these patients. To date, we know very little about the causes of PASC and do not have any understanding of whether pre-existing health issues (risk factors) can be used to predict whether someone will develop PASC or whether individuals with particular risk factors will develop PASC with a specific set of symptoms. The goal of this supplement is to determine whether metabolic changes associated with pre- existing obesity and Type II Diabetes (T2D) contribute to specific PASC-associated immune manifestations. In this supplement, we will test the hypothesis that metabolic risk factors can be used to identify patients with an inflammatory PASC syndrome that is characterized by persistent immune activation. To meet these goals, we have assembled >4000 consented participants (Enterprise cohort) who were previously hospitalized for COVID- 19 infection. We have access to their electronic medical records, can follow their symptoms longitudinally with on-line questionnaires and can obtain biologic samples from them. We have bio-banked blood samples, collected during the acute infection, from >1700 individuals, many of whom were diagnosed with PASC and have been followed longitudinally in our PASC clinic. Using these samples as well as additional blood samples that will be collected from PASC patients in the Enterprise cohort, we propose to: (i) determine whether obese and T2D PASC patients exhibit sustained anti-viral T and B cell responses; (ii) examine whether metabolic risk factors and inflammatory mediators linked to obesity and T2D correlate with the development of inflammatory PASC; and (iii) assess whether pre-existing obesity and associated metabolic disease predict the development of an inflammatory PASC syndrome. These studies are important as they will allow us to specifically interrogate the metabolic and immunologic factors that influence the pathophysiology of PASC in individuals with chronic co- morbidities that affect a large proportion of the population in the Deep South. In the future, we expect that insights gained from these studies may improve the PASC diagnosis and treatment.

尽管人们通常认为冠状病毒会引起急性呼吸道感染，但新的证据表明 病毒抗原甚至完整的病毒可能会在呼吸系统外长期存在 急性感染后的一段时间。此外，数据显示，许多非呼吸道组织， 包括脂肪组织，可以作为病毒的储存库，表明这种感染可能会长期存在 对身体多个器官系统的影响。现在人们认识到很大一部分人 被诊断患有 COVID-19 的人将继续表现出一系列使人衰弱的症状，统称为 作为 SARS-CoV-2（PASC 或 Long-COVID）的急性后遗症，感染后数周至数月。鉴于 大量 SARS-CoV-2 感染者可能出现 PASC，因此迫切需要 更好地了解与不同 PASC 表现相关的风险因素并制定 采取适当的干预措施来治疗这些患者。迄今为止，我们对 PASC 的原因知之甚少， 不了解是否可以使用先前存在的健康问题（风险因素）来预测是否可以 有人会患上 PASC，或者具有特定风险因素的个人是否会患上具有特定风险因素的 PASC 一组症状。该补充剂的目的是确定代谢变化是否与预治疗相关。 现有的肥胖和 II 型糖尿病 (T2D) 会导致特定的 PASC 相关免疫表现。在 在本补充材料中，我们将检验代谢危险因素可用于识别患有以下疾病的患者的假设： 炎症性 PASC 综合征，其特征是持续的免疫激活。为了实现这些目标，我们 已经聚集了超过 4000 名之前因新冠肺炎住院的同意参与者（企业队列） 19 感染。我们可以访问他们的电子病历，可以纵向跟踪他们的症状 在线调查问卷并可以从中获取生物样本。我们有生物库血液样本，收集 在急性感染期间，来自超过 1700 名个体，其中许多人被诊断患有 PASC 并已被 在我们的 PASC 诊所进行纵向随访。使用这些样本以及将要进行的其他血液样本 从 Enterprise 队列中的 PASC 患者中收集数据，我们建议：(i) 确定是否患有肥胖和 T2D PASC 患者表现出持续的抗病毒 T 和 B 细胞反应； (ii) 检查是否存在代谢危险因素 与肥胖和 T2D 相关的炎症介质与炎症 PASC 的发展相关； (iii) 评估先前存在的肥胖和相关代谢疾病是否预示着肥胖的发生 炎症性 PASC 综合征。这些研究很重要，因为它们将使我们能够专门询问 影响慢性共病患者 PASC 病理生理学的代谢和免疫因素 影响南方腹地大部分人口的疾病。未来，我们期望洞察 从这些研究中获得的成果可能会改善 PASC 的诊断和治疗。