期刊
NATURE
卷 589, 期 7841, 页码 270-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-2901-9
关键词
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资金
- Department of Surgery, Weill Cornell Medicine
- American Diabetes Association [7-20-COVID-211]
- NIDDK [R01 DK124463, DP3 DK111907-01, R01 DK116075-01A1, R01 DK119667-01A1, R01DK121072, 1RO3DK117252]
- NCI [R01CA234614]
- NIAID [2R01AI107301]
- Department of Medicine, Weill Cornell Medicine
- NIH [4R00CA226353-02]
- Defense Advanced Research Projects Agency [W911NF-16-C-0050]
- Marc Haas Foundation
- Jack Ma Foundation
Researchers have developed lung and colonic organoid models using human pluripotent stem cells, which demonstrate susceptibility to SARS-CoV-2 infection. These models are valuable for studying the infection of the virus and screening drugs, with potential therapeutic implications for COVID-19.
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.
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