Interactions between neutrophils and cholangiocytes in alcoholic hepatitis

由SARS-CoV-2病毒引起的COVID-19大流行始于2019年秋末，现在已经蔓延 在世界的大部分地区。在撰写本文时，全世界有超过5亿例病例，其中包括80多例 在美国，大约有987，000人死于感染。我们分析了 1，827名COVID-19患者在我们的机构住院，发现肝脏通常参与- AST是 在我们的患者中超过80%升高，而ALT在超过60%的患者中升高，并且感染患者的ALT升高 转氨酶死亡的可能性几乎是其他酶的两倍。我们随后的临床病理研究进一步表明， 大多数死亡的患者表现为肝脏脂肪变性和炎症。此外，现在认识到， 既存酒精相关性肝病（AALD），通常包括脂肪性肝炎，是一种独立的 增加死亡率两倍以上的危险因素。尽管大多数死于COVID-19的患者没有 肝衰竭，这些发现反而提高了AALD中发生的脂肪性肝炎导致 促炎性血栓形成状态导致心肺并发症，通常会导致 更严重，往往是致命的过程。这个项目的目标是确定是否以及如何酒精 脂肪性肝炎与SARS-CoV-2感染协同作用，加剧与 更糟糕的结果，最终目的是确定治疗靶点以阻断这种协同作用。具体 有待检验的假设是SARS-CoV-2感染在AALD的情况下导致病理性白色血细胞 （WBC）-肝细胞相互作用，导致炎性细胞因子的释放明显超过 由SARS-CoV-2感染或AALD单独引起。为了验证这一点，我们将确定白色血细胞是否 白细胞（WBC）是导致COVID-19肝损伤的原因，如果是这样，确定哪种类型的WBC是负责的。我们 还将确定SARS-CoV-2病毒是否对肝细胞造成直接的细胞病变损伤，以及是否 如果肝细胞具有脂肪变性或已经暴露于酒精，则肝细胞更容易受到损伤。这 假设将通过三个具体目标进行测试：（1）我们将确定是否和哪种类型的白细胞 从COVID-19感染的患者与人肝细胞相互作用;（2）我们将确定是否脂肪变性或 其他细胞内因子使肝细胞对SARS-CoV-2病毒的损伤敏感和/或增强 细胞因子释放;（3）基于这些结果，我们将鉴定肝细胞中激活的信号通路 通过白细胞和直接病毒进入，导致COVID-19中肝细胞损伤和细胞因子释放 感染这个项目可能会对我们理解酒精消费如何影响 通过确定COVID-19 AALD患者死亡率增加的机制来确定COVID-19结局。 PI是一位经验丰富的肝细胞生物学家和执业肝病学家，他的主要合作者是肝炎 具有特定SARS-CoV-2专业知识的病毒学家，他们将利用耶鲁大学NIH赞助的肝脏 中心，因此环境也非常适合支持此项目。

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, began in late fall of 2019 and now has spread throughout most of the world. As of this writing, there are over 500 million cases worldwide, including over 80 million cases in the US, approximately 987,000 of whom have died from the infection. We analyzed the first 1,827 patients hospitalized with COVID-19 at our institution and found that the liver is usually involved – AST is elevated in over 80% of our patients, while ALT is elevated in over 60% - and infected patients with elevated transaminases are nearly twice as likely to die. Our subsequent clinical-pathological study furthermore showed that most patients who died exhibited hepatic steatosis and inflammation. In addition, it is now appreciated that pre-existing alcohol-associated liver disease (AALD), which typically includes steatohepatitis, is an independent risk factor that increases mortality more than two-fold. Although most patients who die of COVID-19 do not have liver failure, these findings instead raise the possibility that the steatohepatitis that occurs in AALD results in the pro-inflammatory, thrombogenic state responsible for the cardiopulmonary complications that usually cause a more severe and often fatal course. The goal of this project is to determine whether and how alcoholic steatohepatitis synergizes with SARS-CoV-2 infection to exacerbate the pro-inflammatory state associated with a worse outcome, with the ultimate aim of determining therapeutic targets to block this synergy. The specific hypothesis to be tested is that SARS-CoV-2 infection in the setting of AALD causes pathological white blood cell (WBC)-hepatocyte interactions that result in release of inflammatory cytokines markedly exceeding what is caused by SARS-CoV-2 infection or AALD alone. In order to test this, we will ascertain whether white blood cells (WBCs) are responsible for COVID-19 liver damage, and if so, determine which type of WBC is responsible. We also will determine whether the SARS-CoV-2 virus causes direct cytopathic damage to hepatocytes, and whether the hepatocytes are more susceptible to damage if they have steatosis or have been exposed to alcohol. This hypothesis will be tested through three specific aims: (1) We will determine whether and which type of WBCs from COVID-19-infected patients interact with human hepatocytes; (2) We will determine whether steatosis or other intracellular factors make hepatocytes susceptible to damage from the SARS-CoV-2 virus and/or potentiate cytokine release; and (3) Based on these results, we will identify the signaling pathways activated in hepatocytes by WBCs and by direct viral entry that result in hepatocellular damage and cytokine release in COVID-19 infection. This project may have a broad impact on our understanding of how alcohol consumption affects COVID-19 outcomes by determining the mechanism for increased mortality in COVID-19 patients with AALD. The PI is an experienced liver cell biologist and a practicing hepatologist, his primary collaborator is a hepatitis virologist with specific SARS-CoV-2 expertise, and they will take advantage of Yale's NIH-sponsored Liver Center, so the environment is uniquely suited to support this project as well.