TY - JOUR
KW - Animals
KW - Antiviral Agents
KW - COVID-19
KW - COVID-19 Drug Treatment
KW - Colon
KW - Drug Approval
KW - Drug Evaluation, Preclinical
KW - Female
KW - Heterografts
KW - Humans
KW - In Vitro Techniques
KW - Lung
KW - Male
KW - Mice
KW - organoids
KW - SARS-CoV-2
KW - United States
KW - United States Food and Drug Administration
KW - Viral Tropism
KW - Virus Internalization
AU - Yuling Han
AU - Xiaohua Duan
AU - Liuliu Yang
AU - Benjamin E. Nilsson-Payant
AU - Pengfei Wang
AU - Fuyu Duan
AU - Xuming Tang
AU - Tomer M. Yaron
AU - Tuo Zhang
AU - Skyler Uhl
AU - Yaron Bram
AU - Chanel Richardson
AU - Jiajun Zhu
AU - Zeping Zhao
AU - David Redmond
AU - Sean Houghton
AU - Duc-Huy T. Nguyen
AU - Dong Xu
AU - Xing Wang
AU - Jose Jessurun
AU - Alain Borczuk
AU - Yaoxing Huang
AU - Jared L. Johnson
AU - Yuru Liu
AU - Jenny Xiang
AU - Hui Wang
AU - Lewis C. Cantley
AU - Benjamin R. tenOever
AU - David D. Ho
AU - Fong Cheng Pan
AU - Todd Evans
AU - Huanhuan Joyce Chen
AU - Robert E. Schwartz
AU - Shuibing Chen
AB - 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.
BT - Nature
DA - 2021-01
DO - 10.1038/s41586-020-2901-9
IS - 7841
LA - eng
N2 - 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.
PY - 2021
SP - 270
EP - 275
T2 - Nature
TI - Identification of SARS-CoV-2 inhibitors using lung and colonic organoids
VL - 589
SN - 1476-4687
ER -