GSE160231
hPSC-derived Airway Organoids-based Screen Reveals the Role of HIF1/Glycolysis Axis in SARS-CoV-2 Infection [scRNA-seq]
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 HIF1a, which is further validated by chemotin, another HIF1a 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 HIF1a-glycolysis axis in SARS-CoV-2 infection, which provides a target pathway for anti-viral drug development. Overall design: HPSCs were differentaited to airway organoids. The airway organoids were sequeneced using 10X platform.