Effect of Alcohol Consumption on Molecular Risk Factors for SARS-CoV-2

饮酒对 SARS-CoV-2 分子危险因素的影响

• 批准号: 10186410
• 负责人: URSZULA T IWANIEC
• 金额: $ 7.37万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186410
• 关键词: 2019-nCoV; Adipocytes; Administrative Supplement; Age; Alcohol consumption; Alcohols; Androgens; Archives; Bone Marrow; COVID-19; Cardiovascular Diseases; Cell Membrane Proteins; Cells; Clinical Distribution; Complex; Coronavirus; Data; Dietary Alcohol; Disease; Drug Targeting; Enzymes; Etiology; Female; Funding; Gene Expression; Genetic Transcription; Grant; Health; Heavy Drinking; Hepatocyte; Hormones; Human; Hypertension; Immune response; Immune system; Immunomodulators; Individual; Infection; Insulin-Like Growth Factor I; Intrinsic factor; Knowledge; Leptin; Libraries; Life; Literature; Liver; Lung; Macaca; Macaca mulatta; Mediating; Membrane Proteins; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Oregon; Organ; Outcome; Parents; Pattern; Peptide Hydrolases; Peptidyl-Dipeptidase A; Pharmacological Treatment; Plasma; Primates; Proteins; Research; Risk; Risk Factors; Serine Protease; Severities; Severity of illness; Signal Transduction; Site; Somatotropin; Surface; Symptoms; Systems Analysis; TMPRSS2 gene; Testing; Time; Tissues; Viral; Virus; Virus Diseases; Virus Replication; Weight; abdominal fat; alcohol effect; base; behavioral study; bone; bone health; comorbidity; cytokine; design; drinking; drinking behavior; experience; high risk; infection risk; insight; lifestyle factors; male; nonhuman primate; off-label use; protein expression; receptor; response; sex

PROJECT SUMMARY SARS-CoV-2, the viral cause of Coronavirus Disease 2019 (COVID-19), is a highly contagious coronavirus, which upon infection results in a non-uniform distribution of clinical response. SARS-CoV-2 infects the lung and other organs, including liver and immune system, with non-lung infections contributing to the etiology of severe COVID-19. Co-morbidity factors associated with poorer health outcomes include male sex, older age, and disease. However, these do not fully explain the distribution of COVID-19 severity, suggesting additional modifying factors. Based on the molecular mechanisms mediating viral infection, excessive alcohol consumption may be an unrecognized factor influencing SARS-CoV-2 infection. Spike proteins on the surface of SARS-CoV-2, and host serine proteases (such as furin and TMPRSS2) and ACE2-expressing receptor sites on target cells are required for SARS-CoV-2 infection. Conversely, ADAM17 (TACE), a major sheddase of ACE2, may lower infection. There is strong circumstantial evidence that alcohol directly increases risk for COVID-19 by altering levels of the enzymes and membrane proteins essential for SARS-CoV-2 infection. Growth hormone/ insulin-like growth factor-1 (GH/IGF-1) and androgen signaling are disturbed by alcohol. GH/IGF-1 signaling is important for regulating levels of furin and ACE2. Androgen signaling is the only known regulator of TMPRSS2 gene transcription, suggesting a plausible mechanism for male sex as a risk factor for severe COVID-19. Additionally, alcohol lowers ADAM17 levels and increases levels of the adipocyte-derived hormone leptin; Adam17 and leptin are important modulators of immune response to viral infection. Based on the literature and preliminary data, we hypothesize alcohol consumption results in undesirable levels of plasma and target cell membrane proteins necessary for or opposing SARS-CoV-2 infection. To test this hypothesis, we propose one Specific Aim: Evaluate the effects of alcohol – in the context of sex, age, and weight – on protein and/or gene expression levels of molecular factors influencing SARS-CoV-2 infection (e.g., ACE2, furin, TMPRSS2 and ADAM17) in archived tissues (plasma, lung, liver, abdominal fat, and bone marrow) from male and female rhesus macaques. The macaques were subjected to voluntary alcohol intake that mimics the full range of human drinking behavior (www.MATRR.com). The proposed research will provide insight into alcohol consumption as a potential life-style factor for increasing risk for infection by SARS-CoV-2 and contributing to poorer health outcomes following infection. The research will also help identify potential interactions between alcohol consumption and intrinsic factors such as sex, age and weight in influencing COVID-19 outcome. The requested supplement is a logical extension of the parent proposal (R01AA026289: Complex Systems Analysis of the Impact of Alcohol on Bone in Non-Human Primates) designed to: (1) determine the contribution of invariant intrinsic factors (e.g., age, sex, species) and variable extrinsic factors (e.g., drinking pattern) on organ effects of alcohol (original focus on bone), and (2) identify the contribution of hormones/cytokines.

项目摘要 SARS-COV-2是2019年冠状病毒病的病毒原因（Covid-19），是一种高度传染性的冠状病毒， 感染后导致临床反应的不均匀分布。 SARS-COV-2感染了肺， 其他器官，包括肝脏和免疫系统，非肺部感染有助于严重的病因 新冠肺炎。与健康结果较差有关的合并症因素包括男性，年龄较大和 疾病。但是，这些并不能完全解释Covid-19的严重性的分布，这表明了其他 修改因素。基于介导病毒感染的分子机制，超过酒精 消费可能是未识别的因素影响SARS-COV-2感染。表面上的尖峰蛋白 SARS-COV-2和宿主串行蛋白酶（例如FURIN和TMPRSS2）和表达ACE2的接收器位点 SARS-COV-2感染需要靶细胞。相反，ADAM17（TACE） ACE2，可能会降低感染。有强烈的间接证据表明酒精直接增加了 通过改变SARS-COV-2感染必不可少的酶和膜蛋白的水平来改变COVID-19。 生长骑马/胰岛素样生长因子1（GH/ IGF-1）和雄激素信号传导受到酒精的干扰。 GH/IGF-1信号对于控制FURIN和ACE2的水平很重要。雄激素信号传导是唯一已知的 TMPRSS2基因转录的调节剂，这表明男性性别的合理机制是一种风险因素 严重的Covid-19。此外，酒精可降低ADAM17水平，并增加脂肪细胞的水平 马龙瘦素; ADAM17和瘦素是对病毒感染的免疫反应的重要调节剂。基于 文献和初步数据，我们假设饮酒会导致血浆的水平不足 以及针对SARS-COV-2感染所必需或反对的靶细胞膜蛋白。为了检验这一假设， 我们提出了一个具体目标：在性别，年龄和体重的背景下，评估酒精的影响 影响SARS-COV-2感染的分子因子的蛋白质和/或基因表达水平（例如ACE2，Furin， 从雄性的存档组织（血浆，肺，肝，腹部脂肪和骨髓）中的TMPRSS2和ADAM17） 和雌性恒河猕猴。猕猴受到自愿饮酒，以模仿完整的 人类饮酒行为范围（www.matrr.com）。拟议的研究将提供对酒精的见解 消费是增加SARS-COV-2感染风险的潜在生活方式因素，并有助于 感染后健康结果较差。该研究还将有助于确定潜在的互动 饮酒和内在因素，例如性别，年龄和体重影响共同结果。这 请求的补充是父求的逻辑扩展（R01AA026289：复杂系统 分析酒精对非人类灵长类动物骨骼的影响）设计为：（1）确定贡献 不变的内在因素（例如，年龄，性别，物种）和可变的外部因素（例如，饮酒方式） 酒精的器官作用（原始对骨骼的重点），以及（2）确定激素/细胞因子的贡献。