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Identification of SARS-CoV-2 inhibitors using lung and colonic organoids #MMPMID33116299
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
Nature 2021[Jan]; 589 (7841): 270-275 PMID33116299show ga
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.
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Nature 2021 ; 589 (7841): 270-275
