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Updated: Oct 14, 2025
Establishing Human Lung Organoids and Proximal Differentiation to Generate Mature Airway Organoids
Published on: March 23, 2022
An airway organoid-based screen identifies a role for the HIF1α-glycolysis axis in SARS-CoV-2 infection
Xiaohua Duan1, Xuming Tang2, Manoj S Nair3
1Department 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.
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.
Insights
Researchers developed human airway organoids to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. They identified GW6471, a compound inhibiting the HIF1α-glycolysis axis, which blocks SARS-CoV-2 entry into airway cells.
Area of Science:
- Virology
- Stem Cell Biology
- Respiratory Medicine
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant global health threat.
- Developing accurate disease models is crucial for understanding SARS-CoV-2 infection mechanisms.
- Human airway epithelial cells are a primary target for SARS-CoV-2.
Purpose of the Study:
- To establish a human airway organoid model for SARS-CoV-2 infection studies.
- To identify host factors and pathways essential for SARS-CoV-2 replication.
- To discover potential therapeutic compounds targeting SARS-CoV-2 infection.
Main Methods:
- Derivation of airway organoids from human pluripotent stem cells (hPSC-AOs).
- High-content screening of compounds to identify SARS-CoV-2 inhibitors.
- RNA sequencing (RNA-seq) and metabolic profiling to elucidate mechanisms of action.
- Validation using chemical inhibitors and genetic perturbations.
Main Results:
- hPSC-AOs, particularly ciliated cells, are susceptible to SARS-CoV-2 infection.
- GW6471 was identified as a potent inhibitor of SARS-CoV-2 and B.1.351 variant infection.
- GW6471 inhibits SARS-CoV-2 by targeting the hypoxia-inducible factor 1 subunit alpha (HIF1α)-glycolysis axis.
- Compounds suppressing fatty acid biosynthesis also demonstrated antiviral activity.
Conclusions:
- hPSC-derived airway organoids provide a robust platform for studying SARS-CoV-2 pathogenesis.
- The HIF1α-glycolysis axis is a critical pathway mediating SARS-CoV-2 infection in human airway epithelium.
- GW6471 and other identified compounds represent potential therapeutic strategies against SARS-CoV-2.
