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Identification of SARS-CoV-2 inhibitors using lung and colonic organoids

诱导多能干细胞 类有机物 医学 药品 2019年冠状病毒病(COVID-19) 生物 药理学 免疫学 疾病 严重急性呼吸综合征冠状病毒2型(SARS-CoV-2) 病毒学 内科学 胚胎干细胞 传染病(医学专业) 基因 生物化学 遗传学
作者
Yuling Han,Xiaohua Duan,Liuliu Yang,Benjamin E. Nilsson-Payant,Pengfei Wang,Fuyu Duan,Xiaoxue Tang,Tomer M. Yaron,Tuo Zhang,Skyler Uhl,Yaron Bram,Chanel Richardson,Jiajun Zhu,Zeping Zhao,David Redmond,Sean Houghton,Duc-Huy T. Nguyen,Dong Xu,Xing Wang,José Jessurun,Alain Borczuk,Yaoxing Huang,Jared L. Johnson,Yuru Liu,Jenny Xiang,Hui Wang,Lewis C. Cantley,Benjamin R. tenOever,David D. Ho,Fong Cheng Pan,Todd Evans,Huanhuan Joyce Chen,Robert E. Schwartz,Shuibing Chen
出处
期刊:Nature [Springer Nature]
卷期号:589 (7841): 270-275 被引量:428
标识
DOI:10.1038/s41586-020-2901-9
摘要

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 outcomes1. 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.
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