Transcriptional and non-transcriptional functions of IRF3 in ALD

IRF3 在 ALD 中的转录和非转录功能

• 批准号: 10430300
• 负责人: LAURA E. NAGY
• 金额: $ 16.09万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430300
• 关键词: Acceleration; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcoholic Liver Diseases; Anti-Inflammatory Agents; Antiviral Agents; Antiviral Response; Apoptosis; Apoptotic; BAX gene; Bax protein; Cells; Cessation of life; Chronic; Cirrhosis; Complex; DNA; Data; Development; Double-Stranded RNA; Elements; Ethanol; Exhibits; Failure; Fibrosis; Genes; Genetic Transcription; Hepatic; Hepatitis; Homeostasis; IRF3 gene; Immune; Immune response; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Interferons; Knock-in Mouse; Ligands; Liver; Lysine; Mediating; Mitochondria; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Population; Proteins; Regulation; Reporter; Research Personnel; Resolution; Role; Signal Pathway; Signal Transduction; Stimulator of Interferon Genes; TLR4 gene; Therapeutic Intervention; Tissues; Ubiquitination; Viral Physiology; Virus Diseases; alcohol exposure; alcohol response; cellular targeting; chronic inflammatory disease; ds-DNA; experimental study; hepatocellular injury; improved; injury and repair; liver injury; macrophage; member; microbial; migration; monocyte; mortality; mouse model; novel; prevent; pro-apoptotic protein; receptor; recruit; response; therapeutic target; transcription factor

ABSTRACT Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2) is a highly contagious and fast-spreading infectious disease, which reached pandemic status in only four months and is spreading worldwide with millions of people being affected. The clinical spectrum of COVID-19 ranges from mild to critically ill diseases. COVID-19 can progress rapidly into acute respiratory distress syndrome (ARDS), multiorgan failure, and even death. In the midst of the COVID-19 epidemic, there is some evidence for increased alcohol purchases. Since people generally buy more alcohol during epidemics, increased alcohol consumption may result in reduced resistance to infections like COVID-19 and promote the progression of the disease. SARS-COV-2 is a positive-sense single stranded RNA (ssRNA). While alcohol consumption has not yet been shown to directly increase risk for SARS-COV-2 transmission or COVID-19 severity, alcohol negatively affects the both the innate and adaptive immune systems and increases risk for many infectious diseases. Importantly, recent data from both murine models of ethanol exposure and peripheral blood mononuclear cells (PBMCs) from patients with alcohol-associated hepatitis (AH) indicate that signaling by viral ss/dsRNA is disrupted by alcohol, analogous to impact of alcohol on signaling via bacterial products, such as LPS. The parent RO-1 (Transcriptional and non-transcriptional roles of IRF3 in ALD) for this URGENT COMPETITIVE RENEWAL, we are investigating the impact of chronic ethanol on ss/ds RNA sensing and activation of IRF3-mediated cellular responses. Here we propose to extend the scope of this RO1 to address two important aspects of the interaction of alcohol and COVID-19 in people consuming alcohol. In Specific Aim 1, making use of data from the UK Biobank, we will ask whether alcohol consumption or alcohol-related diseases increase risk of infection, hospitalization and mortality. In Specific Aim 2, we will use single cell RNA seq analysis to interrogate the impact of alcohol consumption on anti-viral responses in peripheral innate and adaptive immune cells. Understanding the impact of alcohol use on risk for COVID-19 and characterizing the specific cellular changes in anti-viral responses will meet an important unmet clinical need for guiding public health and medical responses to the COVID-19 pandemic.

抽象的 2019 年冠状病毒病 (COVID-19) 由严重急性呼吸系统综合症冠状病毒 (SARS- CoV-2）是一种具有高度传染性和快速传播的传染病，仅在四年内就达到了大流行状态 几个月来，正在全球范围内蔓延，数百万人受到影响。 COVID-19 的临床谱 疾病范围从轻症到重症。 COVID-19 可迅速发展为急性呼吸窘迫综合征 (ARDS)、多器官衰竭，甚至死亡。在 COVID-19 流行期间，有一些证据表明 增加酒类购买量。由于人们在流行病期间通常会购买更多的酒，因此饮酒量增加 食用可能会导致对 COVID-19 等感染的抵抗力降低，并促进疾病的进展 疾病。 SARS-COV-2 是一种正义单链 RNA (ssRNA)。虽然饮酒量并未 尚未被证明会直接增加 SARS-COV-2 传播或 COVID-19 严重程度的风险，酒精会产生负面影响 影响先天性和适应性免疫系统，并增加许多传染病的风险。 重要的是，来自乙醇暴露小鼠模型和外周血单核细胞的最新数据 来自酒精相关性肝炎 (AH) 患者的 (PBMC) 表明，病毒 ss/dsRNA 的信号传导是 被酒精破坏，类似于酒精对细菌产物（如脂多糖）信号传导的影响。家长 RO-1（IRF3 在 ALD 中的转录和非转录作用）用于这种紧急的竞争性更新， 我们正在研究长期乙醇对 ss/ds RNA 传感和 IRF3 介导的细胞激活的影响 回应。在此，我们建议扩展 RO1 的范围，以解决交互的两个重要方面 饮酒者中的酒精和 COVID-19。在具体目标 1 中，利用来自英国的数据 生物银行，我们会询问饮酒或酒精相关疾病是否会增加感染风险， 住院率和死亡率。在具体目标 2 中，我们将使用单细胞 RNA seq 分析来探讨影响 饮酒对外周先天性和适应性免疫细胞抗病毒反应的影响。理解 饮酒对 COVID-19 风险的影响以及抗病毒药物中特定细胞变化的特征 应对措施将满足重要的未满足的临床需求，以指导公共卫生和医疗应对措施 2019冠状病毒病大流行。