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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cell+Rep 2021 ; 37 (6): 109920 Nephropedia Template TP
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An airway organoid-based screen identifies a role for the HIF1alpha-glycolysis axis in SARS-CoV-2 infection #MMPMID34731648
Duan X; Tang X; Nair MS; Zhang T; Qiu Y; Zhang W; Wang P; Huang Y; Xiang J; Wang H; Schwartz RE; Ho DD; Evans T; Chen S
Cell Rep 2021[Nov]; 37 (6): 109920 PMID34731648show ga
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 (HIF1alpha), which is further validated by chemical inhibitor and genetic perturbation targeting HIF1alpha. 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 HIF1alpha-glycolysis axis in mediating SARS-CoV-2 infection of human airway epithelium.