Mechanisms underlying and consequences of hepatic and intestinal manifestations of COVID-19

Coronavirus disease 2019 (COVID-19) is caused by a severe acute respiratory syndrome induced by an infection with coronavirus (SARS-CoV-2). At present the development of effective therapeutic interventions is limited, as important aspects of COVID-19 pathogenesis remain incompletely understood. Clinical symptoms of respiratory tract SARS-CoV-2 infection include cough and fever. Interestingly, it appears that also the gastrointestinal tract is impacted by SARS-CoV-2. SARS-CoV-2 is detected both in nasal/pharynx swaps and stool of COVID-19 patients, and some studies suggest that SARS-CoV-2 is detectable for extended periods of time in stool, even if it has been cleared from the respiratory tract. Furthermore, COVID-19 patients also frequently suffer from gastrointestinal symptoms including diarrhea or nausea and show increased serum liver transaminases. However, it remains unknown which cells of the gastrointestinal tract or the liver are infected with SARS-CoV-2 and contribute to the presence of SARS-CoV-2 in the stool. Furthermore, the extent and impact of the associated immune responses in liver and intestine are unknown. Our aim is to clarify these important questions. The CRC 841 studies liver and intestinal inflammation, and investigators within the CRC have extensive experience in determining the immune control of infections and consequences for inflammatory diseases of the liver and the GI tract. We will thus use this expertise i) to investigate the ability of SARS-CoV-2 to infect human liver and intestinal cell using organoid systems; ii) to determine the ability of immune cells, in particular NK cells, to recognize SARS-CoV-2-infected intestinal epithelial cells, cholangiocytes and hepatocytes; and iii) to decipher the consequences of SARS-CoV-2 infection on intestinal inflammation and liver inflammation with a focus on CD4+ T helper cells and NK cells. Overall these studies will determine the underlying mechanism for COVID-19 infection and associated inflammation in the digestive tract.