@article{91b6d41234c24d19a59b7ad82af118e8,
title = "An airway organoid-based screen identifies a role for the HIF1α-glycolysis axis in SARS-CoV-2 infection",
abstract = "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.",
keywords = "GW4671, SARS-CoV-2, airway organoid, fatty acid synthesis, high content drug screen, hypoxia-inducible factor 1-alpha",
author = "Xiaohua Duan and Xuming Tang and Nair, {Manoj S.} and Tuo Zhang and Yunping Qiu and Wei Zhang and Pengfei Wang and Yaoxing Huang and Jenny Xiang and Hui Wang and Schwartz, {Robert E.} and Ho, {David D.} and Todd Evans and Shuibing Chen",
note = "Funding Information: This work was supported by the Department of Surgery, Weill Cornell Medicine (T.E. S.C.); Bill and Melinda Gates Foundation (S.C. T.E. R.E.S.) (R01 DK124463, DP3 DK111907-01, R01 DK116075-01A1, R01 DK119667-01A1 to S.C.); NCI (R01CA234614), NIAID (2R01AI107301), and NIDDK (R01DK121072 and 1RO3DK117252), Department of Medicine, Weill Cornell Medicine (R.E.S.); and the Jack Ma Foundation (D.D.H.). S.C. and R.E.S. are supported as Irma Hirschl Trust Research Award Scholars. The Stable Isotope and Metabolomics Core Facility of the Diabetes Research and Training Center (DRTC) of the Albert Einstein College of Medicine is supported by NIH/NCI grant P60DK020541. We are also very grateful for technical support and advice from Harold Skip Ralph of the Microscopy and Image Analysis Core at WCM. S.C. T.E. D.H. R.E.S. and H.W. conceived and designed the experiments. X.D. and X.T. performed organoid differentiation, drug screening, imaging, and qRT-PCR analysis. M.N. P.W. and Y.H. performed SARS-CoV-2-related experiments. T.Z. W.Z. and J.Z. performed the RNA-seq, single-cell RNA (scRNA)-seq, and bioinformatics analyses. Y.Q. performed metabolic profiling and data analysis. R.E.S. is on the scientific advisory board of Miromatrix. T.R.E. and S.C. are the co-founders of OncoBeat. Funding Information: This work was supported by the Department of Surgery, Weill Cornell Medicine (T.E., S.C.); Bill and Melinda Gates Foundation (S.C., T.E., R.E.S.) ( R01 DK124463 , DP3 DK111907-01 , R01 DK116075-01A1 , R01 DK119667-01A1 to S.C.); NCI ( R01CA234614 ), NIAID ( 2R01AI107301 ), and NIDDK ( R01DK121072 and 1RO3DK117252 ), Department of Medicine, Weill Cornell Medicine (R.E.S.); and the Jack Ma Foundation (D.D.H.). S.C. and R.E.S. are supported as Irma Hirschl Trust Research Award Scholars. The Stable Isotope and Metabolomics Core Facility of the Diabetes Research and Training Center (DRTC) of the Albert Einstein College of Medicine is supported by NIH/NCI grant P60DK020541 . We are also very grateful for technical support and advice from Harold Skip Ralph of the Microscopy and Image Analysis Core at WCM. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = nov,
day = "9",
doi = "10.1016/j.celrep.2021.109920",
language = "English (US)",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}
