Journal
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Volume 11, Issue 4, Pages 935-948Publisher
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2020.11.003
Keywords
SARS-CoV-2; COVID-19; Intestinal Organoids; Remdesivir; Famotidine
Categories
Funding
- International Graduate School in Molecular Medicine Ulm
- European Union's Horizon 2020 research and innovation programme (Fight-nCoV) [101003555]
- MWK Baden-Wurttemberg
- DFG [CRC1279, GRK 2254/1]
- Fokus-Forderung COVID-19 [KL 2544/8-1, MU 3115/14-1]
- Deutsche Forschungsgemeinschaft (DFG) 'Sachbeihilfe' [KL 2544/5-1, KL 2544/7-1]
- Deutsche Forschungsgemeinschaft (DFG) 'Heisenberg-Programm' [KL 2544/6-1]
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Human intestinal organoids derived from pluripotent stem cells (PSC-HIOs) have been used to study SARS-CoV-2 infection and drug validation, revealing viral spread in the gut and the inhibitory effect of remdesivir. PSC-HIOs are susceptible to infection and can be rescued by drug testing.
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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