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: 10404924
• 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/10404924
• 关键词: 2019-nCoV; Acute Respiratory Distress Syndrome; Acute-Phase Reaction; Age; Anti-Bacterial Agents; Anti-Inflammatory Agents; Apolipoprotein A-I; Apolipoprotein E; Atherosclerosis; Bacterial Infections; Basic Science; Biological Assay; Biology; COVID-19; COVID-19 assay; COVID-19 impact; 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; Persons; 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; translational therapeutics

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.

COVID-19：HDL在先天免疫和COVID-19心血管保护中的作用 新型冠状病毒（SARS-CoV-2）引起一种称为COVID-19的疾病。对许多人来说，COVID-19 几乎没有症状，但对其他人来说，COVID-19特别危险，发病率和死亡率很高 rates.患有2型糖尿病和动脉粥样硬化性心血管疾病（ASCVD）的人有两次 SARS-CoV-2感染的风险，并且更可能有不良结果。70%的ASCVD患者， 肌钙蛋白升高死于新冠肺炎我们不知道是什么内在因素导致了这些不同的结果。 高密度脂蛋白（HDL）颗粒在先天免疫系统中起着关键作用， 防止病毒和细菌感染。高密度脂蛋白颗粒最为人所知的作用是防止动脉粥样硬化 心血管疾病（ASCVD）。高密度脂蛋白对心血管的保护作用主要由高密度脂蛋白介导， 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相同。这些保护特性围绕着 介导其抗炎和抗氧化功能的HDL相关蛋白。这个目标 该项目的目的是确定HDL如何保护免受SARS-CoV-2感染，并限制炎症反应， COVID-19疾病。肥胖和2型糖尿病（DM 2）导致高脂血症和代谢变化， 损害HDL抗炎和抗氧化功能。我们将确定DM 2是否导致HDL功能障碍， 导致严重的COVID-19后果。 我们的首要假设是HDL的抗病毒特性可以限制SARS-CoV-2感染， 抗炎和抗氧化能力限制了对COVID-19的全身炎症反应。我们有 发起了与马拉尔博士的合作，马拉尔博士是一位免疫学专家，他对COVID-19患者进行了一项大型试验， 去识别样本与去识别EMR结果数据配对。在AIM 1中，我们将测试假设， SARS-CoV-2感染损害HDL的抗氧化和抗炎能力，这些变化可以 可以通过HDL的蛋白质组学特征来预测。我们还与丹尼森博士合作，丹尼森博士是 冠状病毒生物学在AIM 2中，我们将检验HDL可以降低SARS-CoV-2肺感染性的假设 上皮细胞，但COVID-19损害HDL的抗病毒能力，这可以通过Remdesavir改善 治疗在AIM 3中，我们将检验2型糖尿病改变HDL相关蛋白网络的假设 这限制了COVID-19引起的全身性炎症，并防止了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有不良的COVID-19结果。这个项目的一个优点是我们可以 将我们的HDL功能和抗病毒检测与临床结果联系起来。我们的研究将定义蛋白质组特征 对它的抗病毒作用很重要。我们最终的目标是使用HDL导向疗法， 重组Apo-A1肽改善COVID预后。