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An airway organoid-based screen identifies a role for the HIF1α-glycolysis axis in SARS-CoV-2 infection.
Duan, Xiaohua; Tang, Xuming; Nair, Manoj S; Zhang, Tuo; Qiu, Yunping; Zhang, Wei; Wang, Pengfei; Huang, Yaoxing; Xiang, Jenny; Wang, Hui; Schwartz, Robert E; Ho, David D; Evans, Todd; Chen, Shuibing.
  • Duan X; Department of Surgery, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA; State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • Tang X; Department of Surgery, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA.
  • Nair MS; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
  • Zhang T; Genomics Resources Core Facility, Weill Cornell Medicine, New York, NY 10065, USA.
  • Qiu Y; Department of Medicine, Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Zhang W; Genomics Resources Core Facility, Weill Cornell Medicine, New York, NY 10065, USA.
  • Wang P; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
  • Huang Y; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
  • Xiang J; Genomics Resources Core Facility, Weill Cornell Medicine, New York, NY 10065, USA.
  • Wang H; State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: huiwang@shsmu.edu.cn.
  • Schwartz RE; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA; Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA. Electronic address: res2025@med.cornell.edu
  • Ho DD; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: dh2994@cumc.columbia.edu.
  • Evans T; Department of Surgery, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA. Electronic address: tre2003@med.cornell.edu.
  • Chen S; Department of Surgery, Weill Cornell Medicine, 1300 York Ave., New York, NY 10065, USA. Electronic address: shc2034@med.cornell.edu.
Cell Rep ; 37(6): 109920, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1530684
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Organoids / Hypoxia-Inducible Factor 1, alpha Subunit / COVID-19 / Glycolysis / Lung Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Cell Rep Year: 2021 Document Type: Article Affiliation country: J.celrep.2021.109920

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Organoids / Hypoxia-Inducible Factor 1, alpha Subunit / COVID-19 / Glycolysis / Lung Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Cell Rep Year: 2021 Document Type: Article Affiliation country: J.celrep.2021.109920