Pre-exposure Immunologic Health and Linkages to SARS-COV2 Serologic Responses, Endothelial Cell Resilience, and Cardiovascular Complications: Defining the mechanistic basis of high risk endotypes.

暴露前免疫健康及其与 SARS-COV2 血清学反应、内皮细胞弹性和心血管并发症的联系：定义高风险内型的机制基础。

• 批准号: 10680625
• 负责人: Timothy An-thy Chan
• 金额: $ 67.37万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10680625
• 关键词: 2019-nCoV; ACE2; Acute; Adhesions; Affect; Angiotensin II; Antibody Response; Antigen Receptors; B-Cell Activation; Blood Tests; COVID-19; COVID-19 impact; COVID-19 mortality; COVID-19 pneumonia; COVID-19 risk; COVID-19 severity; COVID-19 survivors; Cardiac; Cardiac Myocytes; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cathepsins; Cause of Death; Cells; Cessation of life; Chronic; Clinic; Clinical; Data; Deltastab; Disease; Distant; Down-Regulation; Economics; Endothelial Cells; Endothelium; Enrollment; Failure; Fibrosis; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Glucose; Goals; Health Personnel; Heart; Heart Diseases; Heart failure; Heterogeneity; Human; Immune; Immune System Diseases; Immunologics; Impairment; In Vitro; Individual; Infection; Infection prevention; Inflammation; Inflammatory; Integration Host Factors; Interleukin-6; Intervention; Knowledge; Left Ventricular Dysfunction; Life; Link; Lipoproteins; Longitudinal cohort; Lymphopenia; Magnetic Resonance; Maintenance; Malignant Neoplasms; Measures; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Nature; Nodal; Organ; Outcome; Oxides; Pathway interactions; Patients; Permeability; Phenotype; Pilot Projects; Plasma; Play; Publishing; Recovery; Research; Risk; Risk Factors; Role; SARS-CoV-2 exposure; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; Scanning; Serology; Severities; Shapes; Stimulus; Survivors; Symptoms; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Techniques; Testing; Tissues; Toxic effect; Ventricular Dysfunction; Viral; Viral Pneumonia; Virus; Work; adverse outcome; base; cardiometabolism; cardiovascular disorder risk; cohort; coronavirus disease; cytokine; cytokine release syndrome; cytotoxic; experimental study; gain of function; high risk; immune activation; immune function; immune health; immune system function; improved; international center; monocyte; mortality; multidisciplinary; neutralizing antibody; population health; prevent; prognostic; prospective; recruit; resilience; response; severe COVID-19; single cell sequencing; thrombotic; transcription factor; transcriptomics

Abstract The objective of this proposal is to understand the immunologic foundations of heart disease which can occur as a result of COVID19. Cardiac impairment, when it develops is often fatal, and our hypothesis is that the maintenance of endothelial function is critical to surviving the protracted nature of COVID19 pneumonia, especially in those with reduced or delayed antibody responses. Our first aim will be to analyze those differences in immune function which pre-date infection but appear to impact the risk of fatal COVID. This will be done by enrolling those at high risk for developing COVID19 (frontline healthcare workers), and performing serially assessments of their immunologic function if they develop COVID. We will specifically investigate the mechanisms that link pre-infection inflammatory pathways to protective serologic responses and symptom severity and recovery. Our second aim will be to perform in vitro experiments to assess the requirements for endothelial cell dysfunction and infectivity. We will compare various inflammatory and cardiovascular stimuli which seem to play a role in promoting COVID19-related cardiovascular complications. Our third aim is to characterize immune cells, endothelial cells, and cardiomyocytes in heart tissue from those with COVID19-induced left ventricular dysfunction. Using single cell sequencing techniques, we will determine cellular and molecular signatures that characterize the microenvironment of the COVID19-affected heart, compared to appropriate controls. Our conceptual model is that pre-existing immune dysfunction 1) reduces the efficiency of neutralizing antibody responses, and 2) in conjunction with cardiovascular disease risk factors, induces endothelial downregulation/depletion of nodal regulators which protect against inflammatory insults. This renders endothelial cells unable to withstand COVID-specific stimuli. Once completed, this study will provide the necessary information to improve the identification of those at risk for COVID-related heart disease and develop rationale approaches to improve the improve survival in the setting of COVID.

抽象的 该提案的目的是了解可能发生的心脏病的免疫学基础 由于新冠肺炎 (COVID19)。心脏损伤一旦发生通常是致命的，我们的假设是 维持内皮功能对于在新冠肺炎的长期生存中生存至关重要， 特别是对于那些抗体反应减少或延迟的人。 我们的首要目标是分析那些早于感染但出现的免疫功能差异 影响致命的新冠病毒的风险。这将通过招募那些感染新冠病毒的高风险人群来完成 （一线医护人员），如果他们出现这种情况，则对其免疫功能进行系列评估 冠状病毒。我们将专门研究感染前炎症途径与 保护性血清学反应和症状严重程度和恢复。 我们的第二个目标是进行体外实验来评估内皮细胞的需求 功能障碍和传染性。我们将比较各种似乎起作用的炎症和心血管刺激 在促进与 COVID19 相关的心血管并发症中发挥作用。 我们的第三个目标是表征心脏组织中的免疫细胞、内皮细胞和心肌细胞 患有 COVID19 引起的左心室功能障碍的患者。利用单细胞测序技术，我们将 确定表征受新冠病毒影响的微环境的细胞和分子特征 心脏，与适当的对照相比。 我们的概念模型是，预先存在的免疫功能障碍 1) 降低了中和效率 抗体反应，2) 与心血管疾病危险因素结合，诱导内皮细胞 节点调节因子的下调/耗尽，可防止炎症损伤。这呈现 内皮细胞无法承受新冠病毒特异性刺激。一旦完成，这项研究将提供 必要的信息，以提高对新冠肺炎相关心脏病风险人群的识别，并制定 在新冠肺炎背景下提高生存率的基本原理方法。