COVID-19: HDL's Role in Innate Immunity and Cardiovascular Protection with COVID-19

COVID-19：HDL 在 COVID-19 的先天免疫和心血管保护中的作用

• 批准号: 10153344
• 负责人: John Michael Stafford
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153344
• 关键词: 2019-nCoV; Acute-Phase Reaction; Adult Respiratory Distress Syndrome; Age; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antiviral Agents; Apolipoprotein A-I; Apolipoprotein E; Atherosclerosis; Bacterial Infections; Basic Science; Biological Assay; Biology; COVID-19; COVID-19 assay; COVID-19 mortality; COVID-19 patient; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Cholesterol; Clinical; Clinical Trials; Collaborations; Coronavirus; Dangerousness; Data; Development; Diabetes Mellitus; Disease; Epithelial Cells; Functional disorder; Goals; HIV; HIV Infections; Heart Diseases; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hypertriglyceridemia; Immunology; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Innate Immune System; Interferon-beta; Intrinsic factor; Knowledge; Lead; Lipids; Lipoproteins; Lung; Mediating; Membrane Fusion; Metabolic; Morbidity - disease rate; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Patients; Peptides; Play; Production; Property; Proteins; Proteomics; Recombinants; Risk; Role; Running; SARS-CoV-2 infection; Sampling; Scaffolding Protein; Sepsis; Symptoms; Testing; Therapeutic; Troponin; United States; Veterans; Viral; Virus Diseases; Virus Replication; coronavirus disease; cytokine; high risk; improved; innovation; lipidomics; macrophage; mortality; novel coronavirus; particle; peptidomimetics; protein expression; proteomic signature; response; severe COVID-19; symptomatic COVID-19; systemic inflammatory response; targeted treatment

COVID19: HDL’s Role in Innate Immunity and Cardiovascular Protection with COVID-19 The novel coronavirus (SARS-CoV-2) causes a disease called COVID-19. For many people, COVID-19 has almost no symptoms, yet for others, COVID-19 is particularly dangerous and has high morbidity and mortality rates. People with pre-existing type-2 diabetes and atherosclerotic cardiovascular disease (ASCVD) have twice the risk of SARS-CoV-2 infection and are more likely to have poor outcomes. 70% of patients with ASCVD and elevated troponin die of COVID. We don’t know what intrinsic factors contribute to these disparate outcomes. High Density Lipoprotein (HDL) particles play a critical role in the innate immune system and are protective against viral and bacterial infections. HDL particles best are known for their roles protecting from atherosclerotic cardiovascular disease (ASCVD). The cardiovascular protection conferred by HDL is largely mediated by HDL’s associated proteins, which comprise about half of HDL’s mass. Mechanisms for HDL’s protection from ASCVD are shared with mechanisms for HDL’s protection from viral infections. These protective properties center around the HDL-associated proteins that mediate its anti-inflammatory and antioxidative functions. The goal of this project is to define how HDL may protect from Sars-CoV-2 infection and limit the inflammatory response to COVID-19 illness. Obesity and type-2 diabetes (DM2) lead to hypertriglyceridemia and metabolic changes that impair HDL’s anti-inflammatory and antioxidative functions. We will define if DM2 leads to HDL dysfunction and contributes to severe COVID-19 outcomes. Our overarching hypothesis is that HDL’s antiviral properties can limit SARS-CoV-2 infection and that HDL’s anti-inflammatory and antioxidative capacity limit the systemic inflammatory response to COVID-19. We have initiated a collaboration with Dr. Malall, an immunology expert running a large trial with COVID-19 patients whose de-identified samples are paired with de-identified EMR outcomes data. In AIM1 we will test the hypothesis that SARS-CoV-2 infection impairs HDL’s antioxidative and anti-inflammatory capacities, and that these changes can be predicted by proteomic signatures of HDL. We also have collaboration with Dr. Denison, an expert in coronavirus biology. In AIM2 we will test the hypothesis that HDL can reduce SARS-CoV-2 infectivity of lung epithelial cells, but that COVID-19 impairs HDL’s antiviral capacity, which can be improved with Remdesavir treatment. In AIM3 we will test the hypothesis that type-2 diabetes alters the HDL-associated protein networks that limit systemic inflammation with COVID-19 and protect against SARS-CoV-2 infection. Diabetes and cardiovascular disease are among the most prevalent problems among United States Veterans, making Veterans more likely to have poor COVID-19 outcomes. An asset to this project is that we can relate our HDL function and antiviral assays with clinical outcomes. Our studies will define proteomic signatures from HDL that are important for its antiviral effects. We ultimately aim to use HDL-directed therapies like recombinant Apo-A1 peptides to improve COVID outcomes.

COVID19：HDL与Covid-19的先天免疫和心血管保护中的作用 新型冠状病毒（SARS-COV-2）引起了一种称为Covid-19的疾病。对于许多人来说，Covid-19有 几乎没有症状，对于其他人来说，Covid-19特别危险，发病率和死亡率很高 费率。患有预先存在的2型糖尿病和动脉粥样硬化心血管疾病（ASCVD）的人两次 SARS-COV-2感染的风险更大，结果更可能。 70％的ASCVD患者和 高架肌钙蛋白死亡。我们不知道哪些内在因素会导致这些不同的结果。 高密度脂蛋白（HDL）颗粒在先天免疫系统中起关键作用，并受到保护 针对病毒和细菌感染。 HDL颗粒以保护动脉粥样硬化而闻名的HDL颗粒以其角色而闻名 心血管疾病（ASCVD）。 HDL授予的心血管保护大部分由HDL介导 相关蛋白质，约占HDL质量的一半。 HDL保护ASCVD的机制 与HDL保护免受病毒感染的机制共享。这些受保护的特性围绕着 介导其抗炎和抗氧化功能的HDL相关蛋白。目标的目标 项目将定义HDL如何保护SARS-COV-2感染并限制炎症反应 2019冠状病毒病。肥胖和2型糖尿病（DM2）导致高甘油三酸酯血症和代谢变化 损害HDL的抗炎和抗氧化功能。我们将定义DM2是否导致HDL功能障碍和 促进严重的共同结果。 我们的总体假设是HDL的抗病毒特性可以限制SARS-COV-2感染，而HDL的抗病毒特性 抗炎和抗氧化能力限制了对Covid-19的全身性炎症反应。我们有 与Malall博士合作，Malall博士是一名免疫学专家 取消识别的样品与去识别的EMR结果数据配对。在AIM1中，我们将检验以下假设 SARS-COV-2感染会损害HDL的抗氧化和抗炎能力，并且这些变化可以 通过HDL的蛋白质组学特征预测。我们还与Denison博士合作，专家 冠状病毒生物学。在AIM2中，我们将测试HDL可以减少肺部SARS-COV-2感染的假设 上皮细胞，但共同细胞会损害HDL的抗病毒能力，可以通过Remdesavir改进 治疗。在AIM3中，我们将检验以下假设：2型糖尿病会改变与HDL相关的蛋白质网络 这种限制了与19日的全身性炎症，并预防SARS-COV-2感染。 糖尿病和心血管疾病是美国最普遍的问题之一 退伍军人，使退伍军人更有可能获得19个结果。该项目的资产是我们可以 将我们的HDL功能和抗病毒测定与临床结果相关联。我们的研究将定义蛋白质组学特征 来自HDL对其抗病毒作用很重要。我们最终的目标是使用HDL导向的疗法 重组Apo-A1辣椒可改善相互兴趣的结果。