Identification of SARS-CoV-2 inhibitors using lung and colonic organoids.
Identification of SARS-CoV-2 inhibitors using lung and colonic organoids.
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DOI：
10.1038/s41586-020-2901-9
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发表时间：
2021-01
期刊：
影响因子：
64.8
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Han Y;Duan X;Yang L;Nilsson-Payant BE;Wang P;Duan F;Tang X;Yaron TM;Zhang T;Uhl S;Bram Y;Richardson C;Zhu J;Zhao Z;Redmond D;Houghton S;Nguyen DT;Xu D;Wang X;Jessurun J;Borczuk A;Huang Y;Johnson JL;Liu Y;Xiang J;Wang H;Cantley LC;tenOever BR;Ho DD;Pan FC;Evans T;Chen HJ;Schwartz RE;Chen S
目前迫切需要利用人类疾病相关细胞建立新的模型来研究SARS-CoV-2生物学并促进药物筛选。由于SARS-CoV-2主要感染呼吸道，我们使用人多能干细胞（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，并在SARS-CoV-2感染后显示出强烈的趋化因子诱导，与COVID-19患者中所见相似。其中近25%的患者还伴有胃肠道表现，这与COVID-19的预后恶化有关。因此，我们还产生了互补的hPSC衍生的结肠类器官（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，特别是肠上皮细胞，表达ACE 2，并允许SARS-CoV-2感染。使用hPSC-LO，我们对FDA批准的药物进行了高通量筛选，并鉴定了SARS-CoV-2的进入抑制剂，包括伊马替尼，麦考酚酸（MPA）和盐酸奎纳克林（QNHC）。这些药物在生理相关水平下的治疗显著抑制了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，并为药物筛选提供有价值的资源，以确定候选的COVID-19治疗剂。
There is an urgent need to create novel models using human disease-relevant cells to study SARS-CoV-2 biology and to facilitate drug screening. 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 upon SARS-CoV-2 infection, similar to what is seen in COVID-19 patients. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes. 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 FDA-approved drugs and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid (MPA), and quinacrine dihydrochloride (QNHC). 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.
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人类肺发育和疾病的三维模型来自多能干细胞。
影响因子：
21.3
作者：
Chen YW;Huang SX;de Carvalho ALRT;Ho SH;Islam MN;Volpi S;Notarangelo LD;Ciancanelli M;Casanova JL;Bhattacharya J;Liang AF;Palermo LM;Porotto M;Moscona A;Snoeck HW
通讯作者：
Snoeck HW
影响因子：
23.9
作者：
Jacob A;Morley M;Hawkins F;McCauley KB;Jean JC;Heins H;Na CL;Weaver TE;Vedaie M;Hurley K;Hinds A;Russo SJ;Kook S;Zacharias W;Ochs M;Traber K;Quinton LJ;Crane A;Davis BR;White FV;Wambach J;Whitsett JA;Cole FS;Morrisey EE;Guttentag SH;Beers MF;Kotton DN
通讯作者：
Kotton DN
影响因子：
2.5
作者：
Arikan, Erdal
通讯作者：
Arikan, Erdal
影响因子：
6.3
作者：
Hooshmand, Reza;Aref, Mohammad Reza
通讯作者：
Aref, Mohammad Reza
影响因子：
1.6
作者：
Hooshmand, Reza;Aref, Mohammad Reza;Eghlidos, Taraneh
通讯作者：
Eghlidos, Taraneh