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
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.