Organoid modeling of lung-resident immune responses to SARS-CoV-2 infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE230398 | GEO | 2023/08/08
REPOSITORIES: GEO
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Project description:COVID-19 is a systemic disease involving multiple organs. Human pluripotent stem cells (hPSCs) derived organoids/cells provide insight into cellular tropism and host response, yet the molecular mechanisms regulating SARS-CoV-2 infection remain poorly defined. Here, we systematically examined changes in transcript profiles caused by SARS-CoV-2 infection at different MOIs for airway organoids (AWOs), alveolar organoids (ALOs) and cardiomyocytes (CMs), and identified several genes, including CIART, that are generally implicated in controlling SARS-CoV-2 infection. AWOs, ALOs, and CMs derived from isogenic CIART-/- hPSCs were significantly resistant to SARS-CoV-2 infection, independent of viral entry. Single-cell RNA-seq further validated the decreased levels of SARS-CoV-2 infection in multi-ciliated cells of AWOs. CUT&RUN, ATAC-seq and RNA-seq analyses found that CIART controls SARS-CoV-2 infection at least in part through regulating NR4A1, a gene also identified from the multi-organoid analysis. Finally, transcriptional profiling and pharmacological inhibition revealed that the Retinoid X Receptor (RXR) pathway regulates SARS-CoV-2 infection downstream of CIART/NR4A1. The multi-organoid platform provides potential therapeutic targets for protection against COVID-19 across organ systems.
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Project description:SARS-CoV-2 causes the COVID-19 pandemic. It is urgent to develop disease models to dissect mechanisms regulating 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-seq analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting 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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Project description:COVID-19 is a systemic disease involving multiple organs. Human pluripotent stem cells (hPSCs) derived organoids/cells provide insight into cellular tropism and host response, yet the molecular mechanisms regulating SARS-CoV-2 infection remain poorly defined. Here, we systematically examined changes in transcript profiles caused by SARS-CoV-2 infection at different MOIs for airway organoids (AWOs), alveolar organoids (ALOs) and cardiomyocytes (CMs), and identified several genes, including CIART, that are generally implicated in controlling SARS-CoV-2 infection. AWOs, ALOs, and CMs derived from isogenic CIART-/- hPSCs were significantly resistant to SARS-CoV-2 infection, independent of viral entry. Single-cell RNA-seq further validated the decreased levels of SARS-CoV-2 infection in multi-ciliated cells of AWOs. CUT&RUN, ATAC-seq and RNA-seq analyses found that CIART controls SARS-CoV-2 infection at least in part through regulating NR4A1, a gene also identified from the multi-organoid analysis. Finally, transcriptional profiling and pharmacological inhibition revealed that the Retinoid X Receptor (RXR) pathway regulates SARS-CoV-2 infection downstream of CIART/NR4A1. The multi-organoid platform provides potential therapeutic targets for protection against COVID-19 across organ systems.
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