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.

摘要 这项建议的目的是了解心脏病可能发生的免疫学基础。 作为COVID19的结果。心脏损害，当它发展时通常是致命的，我们的假设是 维持内皮功能是柯萨奇病毒肺炎持久性生存的关键， 尤其是那些抗体反应降低或延迟的患者。 我们的首要目标是分析感染前免疫功能的差异。 以降低致命性COVID的风险。这将通过招募感染COVID19的高危人群来完成 (一线医护人员)，并对他们的免疫功能进行连续评估 科维德。我们将具体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及恢复。 我们的第二个目标将是进行体外实验，以评估内皮细胞的需求 功能障碍和传染性。我们将对各种炎症和心血管刺激进行比较 在促进COVID19相关心血管并发症方面的作用。 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。 有柯萨奇病毒19所致左心功能不全者。使用单细胞测序技术，我们将 确定表征受COVID19影响的微环境的细胞和分子特征 心脏，与适当的对照组相比。 我们的概念模型是，预先存在的免疫功能障碍1)会降低中和效率 抗体反应，以及2)结合心血管疾病危险因素，诱导内皮细胞 下调/耗尽节点调节器，以防止炎症性侮辱。这将呈现 内皮细胞不能抵抗柯萨奇病毒的特异性刺激。一旦完成，这项研究将提供 必要的信息，以改进对COVID相关心脏病高危人群的识别，并制定 在COVID环境下改善患者生存的基本方法。