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.

中文翻译：

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人多能干细胞衍生的肠类器官中SARS-CoV-2复制的药物抑制作用。

背景和目标

COVID-19大流行已蔓延至世界各地，并构成严重的健康风险。虽然大多数患者表现出轻度症状，但下降的肺炎可导致严重的呼吸功能不全。多达50％的患者表现出胃肠道症状，例如腹泻或恶心，这与长时间的症状和严重程度增加密切相关。因此，迫切需要用于理解和验证COVID-19患者肠道中药物效率的模型。

方法

源自多能干细胞（PSC-HIOs）的人类肠道类器官，由于其模仿人类肠道结构的复杂性，已导致前所未有的成功疾病模型，包括胃肠道感染。在这里，我们采用PSC-HIOs来研究SARS-CoV-2的发病机理及其对瑞姆昔韦的抑制作用，后者是研究治疗COVID-19的主要药物之一。

结果

病毒进入受体ACE2和SARS-CoV-2突突蛋白引发蛋白酶TMPRSS2的免疫染色显示在胃肠道中广泛表达，在肠道中最高水平，后者由PSC-HIO忠实地概括。类器官很容易被SARS-CoV-2感染，随后病毒传播到整个PSC-HIO，随后导致类器官退化。但是，SARS-CoV-2备用杯状细胞缺乏ACE2表达。重要的是，我们挑战了PSC-HIO的药物测试能力。具体而言，瑞姆昔韦在低微摩尔浓度下有效剂量依赖性地抑制了SARS-CoV-2感染，并挽救了PSC-HIO形态。

结论

因此，PSC-HIOs是研究SARS-CoV-2感染并鉴定和验证药物的重要工具，尤其是对肠道有潜在作用的药物。