Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE148696 | GEO | 2021/01/01
REPOSITORIES: GEO
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Project description:The SARS-CoV-2 has already caused over twelve million COVID-19 cases and half a million deaths worldwide. There is an urgent need to create novel models using human disease-relevant cells to study SARS-CoV-2 biology and to facilitate drug screening. As SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs) that could be adapted for drug screening. The hPSC-LOs, particularly alveolar type II-like cells, express the viral entry receptor ACE2, are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines and cytokines upon SARS-CoV-2 infection, similar to what is seen in COVID-19 patients. Nearly 25% of these patients 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 FDA-approved drugs and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid (MPA), and quinacrine dihydrochloride (QNHC). Pre- or post-infection 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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Project description:We systematically probed which cell types are permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection of hPSC-derived lung organoids revealed upregulation of chemokines but not type I/III interferon signaling, similar to what was seen in primary human COVID-19 pulmonary infection.
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Project description:The SARS-CoV-2 virus has already caused over a million COVID-19 cases and over fifty-thousand deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 virus using human disease-relevant cells and tissues to understand key features of virus biology. We present a platform comprised of nine different cell and organoid derivatives from human pluripotent stem cells (hPSCs) representing all three primary germ layers, including lung progenitors and alveolar type II (AT2) cells, pancreatic endocrine cells, liver organoids, endothelial cells, cardiomyocytes, macrophages, microglia, and both cortical and dopaminergic neurons. We systematically probed which cell types are permissive to SARS-CoV-2 infection. Human pancreatic beta cells and hepatocytes were strikingly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and liver organoids. Both in vitro and in a humanized mouse model, human lung progenitors and AT2 cells express the ACE2 viral receptor and were highly permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection of hPSC-derived pancreatic and lung organoids revealed upregulation of chemokines but not type I/III interferon signaling, similar to what was seen in primary human COVID-19 pulmonary infection. Therefore, hPSC-derived cells phenocopy human COVID-19 disease and provide a valuable resource to understand SARS-CoV-2 biology and search for novel therapeutics.
2020-06-11 | GSE147903 | GEO
Project description:SARS-CoV-2 causes the COVID-19 pandemic. It is urgent to develop disease models to dissect mechanisms regulating SARS-CoV-2 infection. Here, we derive airway organoids from human pluripotent stem cells (hPSC-AOs). The hPSC-AOs, particularly ciliated-like cells, are permissive to SARS-CoV-2 infection. Using this platform, we perform a high content screen and identify GW6471, which blocks SARS-CoV-2 infection. GW6471 can also block infection of the B.1.351 SARS-CoV-2 variant. RNA-seq analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting HIF1α, which is further validated by chemical inhibitor and genetic perturbation targeting HIF1α. Metabolic profiling identifies decreased rates of glycolysis upon GW6471 treatment, consistent with transcriptome profiling. Finally, xanthohumol, 5-(Tetradecyloxy)-2-furoic acid, and ND-646, three compounds that suppress fatty acid biosynthesis, also block SARS-CoV-2 infection. Together, a high content screen coupled with transcriptome and metabolic profiling reveals a key role of the HIF1α-glycolysis axis in mediating SARS-CoV-2 infection of human airway epithelium.
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Project description:The current COVID-19 pandemic is caused by the novel coronavirus 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 virus 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 often present with respiratory symptoms including cough, dyspnea, and respiratory distress but upwards of 25% of respiratory dysfunction, many COVID-19 patients have digestive system indications, including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with more severe COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of different 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 types of hESC-derived colon cells, but are highly enriched in hPSC-derivedKRT20+ enterocytes. Distinct cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which is further validated in vivo using a humanized mouse model. Finally, we adapted hPSC-derived COs to a high throughput platform to screen 1280 FDA-approved drugs. Mycophenolic acid was found to block the entry of SARS-Cov-2 pseudo-entry virus in COs, and confirmed to block infection of SARS-CoV-2 virus. In summary, 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 a drug suitable for rapid clinical testing that blocks SARS-CoV-2 infection.
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Project description:SARS-CoV-2, the virus causing recently pandemic, primarily infects the respiratory tract. There is an urgent need to develop platforms using disease relevant human cells to dissect the molecular mechanism regulating SARS-CoV-2 infection and perform drug screen. Here, we derived airway organoids from human pluripotent stem cells (hPSC-AO). The hPSC-AOs, particularly ciliated cells, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-AOs, we performed a high content screen and identified GW6471, which blocks SARS-CoV-2 infection. RNA-seq analysis suggested that GW6471 blocking SARS-CoV-2 infection by inhibiting HIF1α, which is further validated by chemotin, another HIF1α inhibitor. Furthermore, metabolic profiling identified that the downregulation of glycolysis upon GW6471 treatment, which is further validated by RNA-seq. Finally, xanthohumol, a prenylated flavonoid suppressing fatty acid and cholesterol biosynthesis, blocks SARS-CoV-2 infection. Together, we applied the high content screen, RNA-seq and metabolic profiling to define the key role of HIF1α-glycolysis axis in SARS-CoV-2 infection, which provides a target pathway for anti-viral drug development.
2023-10-01 | GSE160231 | GEO
Project description:SARS-CoV-2, the virus causing recently pandemic, primarily infects the respiratory tract. There is an urgent need to develop platforms using disease relevant human cells to dissect the molecular mechanism regulating SARS-CoV-2 infection and perform drug screen. Here, we derived airway organoids from human pluripotent stem cells (hPSC-AO). The hPSC-AOs, particularly ciliated cells, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-AOs, we performed a high content screen and identified GW6471, which blocks SARS-CoV-2 infection. RNA-seq analysis suggested that GW6471 blocking SARS-CoV-2 infection by inhibiting HIF1α, which is further validated by chemotin, another HIF1α inhibitor. Furthermore, metabolic profiling identified that the downregulation of glycolysis upon GW6471 treatment, which is further validated by RNA-seq. Finally, xanthohumol, a prenylated flavonoid suppressing fatty acid and cholesterol biosynthesis, blocks SARS-CoV-2 infection. Together, we applied the high content screen, RNA-seq and metabolic profiling to define the key role of HIF1α-glycolysis axis in SARS-CoV-2 infection, which provides a target pathway for anti-viral drug development.
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