There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, as SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes 1 . We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high-throughput screen of drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics. The use of lung and colonic organoid systems to assess the susceptibility of lung and gut cells to SARS-CoV-2 and to screen FDA-approved drugs that have antiviral activity against SARS-CoV-2 is demonstrated.

中文翻译：

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使用肺和结肠类器官鉴定 SARS-CoV-2 抑制剂


迫切需要利用人类疾病相关细胞创建新模型来研究严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 生物学并促进药物筛选。在这里，由于 SARS-CoV-2 主要感染呼吸道，我们使用人类多能干细胞 (hPSC-LO) 开发了肺类器官模型。 hPSC-LO（特别是肺泡 II 型样细胞）允许 SARS-CoV-2 感染，并且在 SARS-CoV-2 感染后表现出强烈的趋化因子诱导作用，类似于在 COVID-19 患者中观察到的情况。这些患者中近 25% 还存在胃肠道表现，这与更糟糕的 COVID-19 结局相关 1 。因此，我们还生成了互补的 hPSC 衍生结肠类器官 (hPSC-CO)，以探索结肠细胞对 SARS-CoV-2 感染的反应。我们发现多种结肠细胞类型，尤其是肠上皮细胞，表达 ACE2，并且允许 SARS-CoV-2 感染。使用 hPSC-LO，我们对 FDA（美国食品和药物管理局）批准的药物进行了高通量筛选，并确定了 SARS-CoV-2 的进入抑制剂，包括伊马替尼、霉酚酸和二盐酸奎纳克林。这些药物以生理相关水平进行治疗可显着抑制 hPSC-LO 和 hPSC-CO 的 SARS-CoV-2 感染。总之，这些数据表明，被 SARS-CoV-2 感染的 hPSC-LO 和 hPSC-CO 可以作为研究 SARS-CoV-2 感染的疾病模型，并为药物筛选提供宝贵的资源，以确定候选的 COVID-19 疗法。证明了使用肺和结肠类器官系统来评估肺和肠道细胞对 SARS-CoV-2 的敏感性，并筛选 FDA 批准的对 SARS-CoV-2 具有抗病毒活性的药物。