Abstract
SummaryIt 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.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease 2019 (COVID-19) pandemic, among the worst global health care crises of our time
The human pluripotent stem cell (hPSC)-derived ciliated-like cell population was enriched for adult human ciliated and proximal ciliated cell markers (Figure 1C)
Correlation analysis of signature genes further validated identity of the hPSC-derived ciliated-like cell population in hPSC-derived airway organoid (hPSC-AO) showing high similarity to adult human ciliated and proximal ciliated cells, but not alveolar epithelial type 1 or type 2 cells (Travaglini et al, 2020) (Figure 1D)
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease 2019 (COVID-19) pandemic, among the worst global health care crises of our time. There is a great and immediate need to develop new and relevant models to study virus biology and virus-host interactions and perform drug screens. Compared with typically used Vero cells (a kidney epithelial cell line derived from the African green monkey) or transformed carcinoma cell lines, human organoids may more faithfully recapitulate key aspects of viral infection and virus-host interactions. We developed an hPSC-derived airway organoid (hPSC-AO) platform for monitoring infection of SARS-CoV-2 and to screen for inhibitors. HPSC-AOs facilitate scaling, which is needed for high-throughput screening of small molecules and metabolic profiling.
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