Transcriptional and non-transcriptional functions of IRF3 in ALD

摘要 严重急性呼吸系统综合症冠状病毒引起的2019年冠状病毒病(新冠肺炎) CoV-2)是一种高传染性和快速传播的传染病，仅在4年内达到大流行状态 几个月的时间里，它正在全球蔓延，数百万人受到影响。新冠肺炎的临床谱分析 从轻微疾病到危重疾病不等。新冠肺炎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。在新冠肺炎疫情肆虐之际，有一些证据表明 增加了酒类购买量。由于人们在流行病期间通常会购买更多的酒，因此增加了酒精 消费可能会降低对新冠肺炎等感染的抵抗力，并促进 疾病。SARS-COV-2是一种正向单链RNA(SsRNA)。而饮酒并没有 但已被证明会直接增加感染SARS-COV-2或新冠肺炎严重程度的风险，饮酒会带来负面影响 影响先天免疫系统和获得性免疫系统，并增加许多传染病的风险。 重要的是，来自酒精暴露的小鼠模型和外周血单核细胞的最新数据 酒精性肝炎(AH)患者的PBMC表明，病毒ss/dsRNA的信号转导 被酒精干扰，类似于酒精对细菌产物(如脂多糖)信号的影响。父辈 RO-1(IRF3在ALD中的转录和非转录作用)用于这种紧迫的竞争更新， 我们正在研究慢性酒精对IRF3介导的细胞ss/ds RNA传感和激活的影响。 回应。在这里，我们建议扩展此RO1的范围，以解决交互的两个重要方面 在饮酒的人中，酒精和新冠肺炎的含量。在具体目标1中，利用英国的数据 生物库，我们将询问饮酒或与酒精相关的疾病是否会增加感染的风险， 住院和死亡率。在具体目标2中，我们将使用单细胞rna序列分析来询问影响。 酒精摄入对外周天然免疫细胞和获得性免疫细胞抗病毒反应的影响。理解 饮酒对新冠肺炎发病风险的影响及其在抗病毒方面的特异性细胞变化特征 应对措施将满足尚未得到满足的重要临床需求，以指导公共卫生和医疗应对措施 新冠肺炎大流行。

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.