An airway organoid-based screen identifies a role for the HIF1α-glycolysis axis in SARS-CoV-2 infection

ABSTRACT: Summary It is urgent to develop disease models to dissect mechanisms regulating severe acute respiratory syndrome coronavirus 2 (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 sequencing (RNA-seq) analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting hypoxia inducible factor 1 subunit alpha (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. Graphical abstract Highlights • hPSC-derived airway organoids (hPSC-AOs) are permissive to SARS-CoV-2 infection• An hPSC-AO-based high content screen identifies GW6471 blocking SARS-CoV-2 infection• Chemical and genetic perturbation of HIF1α blocks SARS-CoV-2 infection• Glycolysis is necessary for SARS-CoV-2 infection of human airway epithelium Duan et al. develop an hPSC-derived airway organoid-based platform to monitor SARS-CoV-2 infection and screen for anti-viral drugs. From a high content chemical screen, they identify GW6471 that blocks SARS-CoV-2 infection in hPSC-derived airway organoids and hPSC-derived colonic organoids by inhibiting the HIF1α-glycolysis axis.

SUBMITTER: Duan X 

PROVIDER: S-EPMC8516798 | biostudies-literature |

REPOSITORIES: biostudies-literature