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

Cellular and Molecular Gastroenterology and Hepatology

Alexander Kleger¹  Thomas Seufferlein²  Sandra Heller²  Jana Krüger²  Thomas F.E. Barth³  Steffen Stenger⁴  Konstantin M.J. Sparrer⁵  Jan Münch⁵  Rüdiger Groß⁵  Janis A. Müller⁵  Lennart Koepke⁵  Carina Conzelmann⁵  Desiree Schütz⁵  Tatjana Weil⁵ 

[1] Correspondence Address correspondence to Jan Münch, Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstrasse 1, 89081 Ulm, Germany. fax: [phone];Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany;Department of Pathology, Ulm University Hospital, Ulm, Germany;Institute for Microbiology and Hygiene, Ulm University Medical Center, Ulm, Germany;Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany;

关键词: SARS-CoV-2;    COVID-19;    Intestinal Organoids;    Remdesivir;    Famotidine;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown