Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids

Duan, X.; Han, Y.; Yang, L.; Nilsson, B.; Wang, P.; Zhang, T.; Wang, X.; Xu, D.; Xiang, J. Z.; uhl, s.; Huang, Y.; Chen, H.; Wang, H.; tenOever, B. R.; Schwartz, R. E.; Ho, D. D.; Pan, F. C.; Chen, S.; Evans, T. R.

doi:10.1101/2020.05.02.073320

bioRxiv · 10.1101/2020.05.02.073320

Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids

Duan, X.·Han, Y.·Yang, L.·Nilsson, B.·Wang, P.·Zhang, T.·Wang, X.·Xu, D.·Xiang, J. Z.·uhl, s.·Huang, Y.·Chen, H.·Wang, H.·tenOever, B. R.·Schwartz, R. E.·Ho, D. D.·Pan, F. C.·Chen, S.·Evans, T. R.

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Abstract

Summary ParagraphThe current COVID-19 pandemic is caused by SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients typically present with respiratory symptoms including cough, dyspnea, and respiratory distress, but nearly 25% of patients have gastrointestinal indications including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with worse COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple hESC-derived colonic cell types, but highly enriched in enterocytes. Multiple cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which was further validated in vivo using a humanized mouse model. We used hPSC-derived COs in a high throughput platform to screen 1280 FDA-approved drugs against viral infection. Mycophenolic acid and quinacrine dihydrochloride were found to block the infection of SARS-CoV-2 pseudo-entry virus in COs both in vitro and in vivo, and confirmed to block infection of SARS-CoV-2 virus. This study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified drugs that blocks SARS-CoV-2 infection, suitable for rapid clinical testing.

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Duan, X., Han, Y., Yang, L., Nilsson, B., Wang, P., Zhang, T., Wang, X., Xu, D., Xiang, J. Z., uhl, s., Huang, Y., Chen, H., Wang, H., tenOever, B. R., Schwartz, R. E., Ho, D. D., Pan, F. C., Chen, S., Evans, T. R.. 2020-05-02. Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids. https://doi.org/10.1101/2020.05.02.073320

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