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

TitleIdentification of SARS-CoV-2 inhibitors using lung and colonic organoids.
Publication TypeJournal Article
Year of Publication2021
AuthorsHan 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 D-HT, 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 FCheng, Evans T, Chen HJoyce, Schwartz RE, Chen S
Date Published2021 01
KeywordsAnimals, Antiviral Agents, Colon, COVID-19, Drug Approval, Drug Evaluation, Preclinical, Female, Heterografts, Humans, In Vitro Techniques, Lung, Male, Mice, Organoids, SARS-CoV-2, United States, United States Food and Drug Administration, Viral Tropism, Virus Internalization

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. 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.

Alternate JournalNature
PubMed ID33116299
PubMed Central IDPMC8034380
Grant ListDP3 DK111907 / DK / NIDDK NIH HHS / United States
R00 CA226353 / CA / NCI NIH HHS / United States
R01 DK119667 / DK / NIDDK NIH HHS / United States
R01 CA234614 / CA / NCI NIH HHS / United States
R01 DK124463 / DK / NIDDK NIH HHS / United States
R03 DK117252 / DK / NIDDK NIH HHS / United States
R01 DK116075 / DK / NIDDK NIH HHS / United States
R01 DK121072 / DK / NIDDK NIH HHS / United States
R01 AI107301 / AI / NIAID NIH HHS / United States
Related Faculty: 
Jose Jessurun, M.D.


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