Cellular and Molecular Gastroenterology and Hepatology (2021-01-01)

Drug Inhibition of SARS-CoV-2 Replication in Human Pluripotent Stem Cell–Derived Intestinal OrganoidsSummary

  • Jana Krüger,
  • Rüdiger Groß,
  • Carina Conzelmann,
  • Janis A. Müller,
  • Lennart Koepke,
  • Konstantin M.J. Sparrer,
  • Tatjana Weil,
  • Desiree Schütz,
  • Thomas Seufferlein,
  • Thomas F.E. Barth,
  • Steffen Stenger,
  • Sandra Heller,
  • Jan Münch,
  • Alexander Kleger

Journal volume & issue
Vol. 11, no. 4
pp. 935 – 948

Abstract

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Background and aims: The COVID-19 pandemic has spread worldwide and poses a severe health risk. While most patients present mild symptoms, descending pneumonia can lead to severe respiratory insufficiency. Up to 50% of patients show gastrointestinal symptoms like diarrhea or nausea, intriguingly associating with prolonged symptoms and increased severity. Thus, models to understand and validate drug efficiency in the gut of COVID-19 patients are of urgent need. Methods: Human intestinal organoids derived from pluripotent stem cells (PSC-HIOs) have led, due to their complexity in mimicking human intestinal architecture, to an unprecedented number of successful disease models including gastrointestinal infections. Here, we employed PSC-HIOs to dissect SARS-CoV-2 pathogenesis and its inhibition by remdesivir, one of the leading drugs investigated for treatment of COVID-19. Results: Immunostaining for viral entry receptor ACE2 and SARS-CoV-2 spike protein priming protease TMPRSS2 showed broad expression in the gastrointestinal tract with highest levels in the intestine, the latter faithfully recapitulated by PSC-HIOs. Organoids could be readily infected with SARS-CoV-2 followed by viral spread across entire PSC-HIOs, subsequently leading to organoid deterioration. However, SARS-CoV-2 spared goblet cells lacking ACE2 expression. Importantly, we challenged PSC-HIOs for drug testing capacity. Specifically, remdesivir effectively inhibited SARS-CoV-2 infection dose-dependently at low micromolar concentration and rescued PSC-HIO morphology. Conclusions: Thus, PSC-HIOs are a valuable tool to study SARS-CoV-2 infection and to identify and validate drugs especially with potential action in the gut.

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