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A Multi-Organoid Platform Identifies CIART as a Key Factor for SARS-CoV-2 Infection [ATAC-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202965 | GEO | 2022/12/07

REPOSITORIES: GEO

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A Multi-Organoid Platform Identifies CIART as a Key Factor for SARS-CoV-2 Infection [bulk RNA-seq]

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.

2022-12-07 | GSE202963 | GEO

A Multi-Organoid Platform Identifies CIART as a Key Factor for SARS-CoV-2 Infection [CUT&RUN]

2022-12-07 | GSE202966 | GEO

A Multi-Organoid Platform Identifies CIART as a Key Factor for SARS-CoV-2 Infection [scRNA-seq]

2022-12-07 | GSE202964 | GEO

A Platform to Define Cellular Targets of SARS-COV-2 Infection Using Human Pluripotent Stem Cell-Derived Cells and Organoids

Project description:The SARS-CoV-2 virus has already caused over a million COVID-19 cases and over fifty-thousand deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 virus using human disease-relevant cells and tissues to understand key features of virus biology. We present a platform comprised of nine different cell and organoid derivatives from human pluripotent stem cells (hPSCs) representing all three primary germ layers, including lung progenitors and alveolar type II (AT2) cells, pancreatic endocrine cells, liver organoids, endothelial cells, cardiomyocytes, macrophages, microglia, and both cortical and dopaminergic neurons. We systematically probed which cell types are permissive to SARS-CoV-2 infection. Human pancreatic beta cells and hepatocytes were strikingly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and liver organoids. Both in vitro and in a humanized mouse model, human lung progenitors and AT2 cells express the ACE2 viral receptor and were highly permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection of hPSC-derived pancreatic and lung organoids revealed upregulation of chemokines but not type I/III interferon signaling, similar to what was seen in primary human COVID-19 pulmonary infection. Therefore, hPSC-derived cells phenocopy human COVID-19 disease and provide a valuable resource to understand SARS-CoV-2 biology and search for novel therapeutics.

2020-06-11 | GSE147903 | GEO

Transcriptomic analysis of human alveolar type II cell organoids post infection of SARS-CoV-2

Project description:We performed unbiased transcriptomic profiling on organoids cultures after SARS-CoV-2 infection to gain insights into AT2s response to SARS-CoV-2 infection.

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RNA-Seq of SARS-Cov-2 Infection in Human Bronchial Epithelium Organoids

Project description:We performed RNA-Seq of SARS-Cov-2 infection in human bronchial epithelium organoids. The organoids were infected with SARS-Cov-2 for 48hours or 72hours respectively, and compared with uninfected mock control.

2021-06-08 | GSE152060 | GEO

RNA-Seq of SARS-Cov-2 Infection in Human Airway Epithelium Organoids

Project description:We performed RNA-Seq of SARS-Cov-2 infection in human airway epithelium organoids. The organoids were infected with SARS-Cov-2 for 24hours or 48hours respectively, and compared with uninfected mock control.

2021-08-07 | GSE155974 | GEO

SARS-CoV-2 infection of Lung Organoids Reveals Conserved Use of Tetraspanin-8 by Ancestral-, Delta-, and Omicron- Variants

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2022-09-30 | GSE211562 | GEO

An Airway Organoid-Based Screen Identifies a Role for the HIF1α-Glycolysis Axis in SARS-CoV-2 Infection

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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Main Postoperative Complications After COVID-19

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