Interactions between neutrophils and cholangiocytes in alcoholic hepatitis

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.