Abstract
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.
Keywords: COVID-19; Famotidine; Intestinal Organoids; Remdesivir; SARS-CoV-2.
【저자키워드】 COVID-19, Famotidine, Remdesivir, SARS-CoV-2., Intestinal Organoids, 【초록키워드】 Treatment, SARS-CoV-2, Pneumonia, SARS-COV-2 infection, COVID-19 pandemic, severity, Human, risk, Symptom, drug, diarrhea, viral spread, viral entry, Spread, Deterioration, Health, SARS-CoV-2 spike protein, intestine, Patient, Disease model, morphology, Drug testing, ACE2 expression, expression, SARS-CoV-2 pathogenesis, gastrointestinal tract, mild symptoms, Concentration, Organoid, COVID-19 patient, Efficiency, Gut, gastrointestinal infections, nausea, priming, protease TMPRSS2, receptor ACE2, while, Gastrointestinal symptom, pluripotent stem cell, intestinal, Goblet cell, highest, identify, investigated, inhibited, dissect, rescued, mimicking, descending, infected with SARS-CoV-2, intestinal organoid, 【제목키워드】 SARS-CoV-2, Human, drug, inhibition, Organoid, STEM,