Identification of Drugs Blocking SARS-CoV-2 Infection using hPSC-derived Lung and Colonic Organoids
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ABSTRACT:
PROVIDER: PRJNA649019 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12334173_1.fastq.gz | Fastqsanger.gz | |||
| SRR12334173_2.fastq.gz | Fastqsanger.gz | |||
| SRR12334174.fastq.gz | Fastqsanger.gz | |||
| SRR12334175.fastq.gz | Fastqsanger.gz | |||
| SRR12334176.fastq.gz | Fastqsanger.gz |
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Project description:The SARS-CoV-2 has already caused over twelve million COVID-19 cases and half a million deaths worldwide. There is an urgent need to create novel models using human disease-relevant cells to study SARS-CoV-2 biology and to facilitate drug screening. As SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs) that could be adapted for drug screening. The hPSC-LOs, particularly alveolar type II-like cells, express the viral entry receptor ACE2, are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines and cytokines upon SARS-CoV-2 infection, similar to what is seen in COVID-19 patients. Nearly 25% of these patients have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes1. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high throughput screen of FDA-approved drugs and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid (MPA), and quinacrine dihydrochloride (QNHC). Pre- or post-infection treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.
2020-08-11 | GSE155241 | GEO
Project description:Identification of Drugs Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colonic Organoids
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Project description:We systematically probed which cell types in the colon are permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection of hPSC-derived colon organoids revealed upregulation of chemokines but not type I/III interferon signaling. A large small molecule screen was also performed.
2021-01-01 | GSE148696 | GEO
Project description:The current COVID-19 pandemic is caused by the novel coronavirus SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 virus biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients often present with respiratory symptoms including cough, dyspnea, and respiratory distress but upwards of 25% of respiratory dysfunction, many COVID-19 patients have digestive system indications, including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with more severe COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of different colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple types of hESC-derived colon cells, but are highly enriched in hPSC-derivedKRT20+ enterocytes. Distinct cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which is further validated in vivo using a humanized mouse model. Finally, we adapted hPSC-derived COs to a high throughput platform to screen 1280 FDA-approved drugs. Mycophenolic acid was found to block the entry of SARS-Cov-2 pseudo-entry virus in COs, and confirmed to block infection of SARS-CoV-2 virus. In summary, this study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified a drug suitable for rapid clinical testing that blocks SARS-CoV-2 infection.
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Project description:SARS-CoV-2, the virus causing recently pandemic, primarily infects the respiratory tract. There is an urgent need to develop platforms using disease relevant human cells to dissect the molecular mechanism regulating SARS-CoV-2 infection and perform drug screen. Here, we derived airway organoids from human pluripotent stem cells (hPSC-AO). The hPSC-AOs, particularly ciliated cells, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-AOs, we performed a high content screen and identified GW6471, which blocks SARS-CoV-2 infection. RNA-seq analysis suggested that GW6471 blocking SARS-CoV-2 infection by inhibiting HIF1α, which is further validated by chemotin, another HIF1α inhibitor. Furthermore, metabolic profiling identified that the downregulation of glycolysis upon GW6471 treatment, which is further validated by RNA-seq. Finally, xanthohumol, a prenylated flavonoid suppressing fatty acid and cholesterol biosynthesis, blocks SARS-CoV-2 infection. Together, we applied the high content screen, RNA-seq and metabolic profiling to define the key role of HIF1α-glycolysis axis in SARS-CoV-2 infection, which provides a target pathway for anti-viral drug development.
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Project description:SARS-CoV-2, the virus causing recently pandemic, primarily infects the respiratory tract. There is an urgent need to develop platforms using disease relevant human cells to dissect the molecular mechanism regulating SARS-CoV-2 infection and perform drug screen. Here, we derived airway organoids from human pluripotent stem cells (hPSC-AO). The hPSC-AOs, particularly ciliated cells, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-AOs, we performed a high content screen and identified GW6471, which blocks SARS-CoV-2 infection. RNA-seq analysis suggested that GW6471 blocking SARS-CoV-2 infection by inhibiting HIF1α, which is further validated by chemotin, another HIF1α inhibitor. Furthermore, metabolic profiling identified that the downregulation of glycolysis upon GW6471 treatment, which is further validated by RNA-seq. Finally, xanthohumol, a prenylated flavonoid suppressing fatty acid and cholesterol biosynthesis, blocks SARS-CoV-2 infection. Together, we applied the high content screen, RNA-seq and metabolic profiling to define the key role of HIF1α-glycolysis axis in SARS-CoV-2 infection, which provides a target pathway for anti-viral drug development.
2023-10-01 | GSE160230 | GEO
Project description:Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively permissive to SARS-CoV-2 infection both in vitro and upon transplantation in vivo, and that SARS-CoV-2 infection triggers a DA neuron inflammatory and cellular senescence response. A high-throughput screen in hPSC-derived DA neurons identified several FDA approved drugs, including riluzole, metformin, and imatinib, that can rescue the cellular senescence phenotype and prevent SARS-CoV-2 infection. RNA-seq analysis of human ventral midbrain tissue from COVID-19 patients, using formalin-fixed paraffin-embedded autopsy samples, confirmed the induction of an inflammatory and cellular senescence signature and identified low levels of SARS-CoV-2 transcripts. Our findings demonstrate that hPSC-derived DA neurons can serve as a disease model to study neuronal susceptibility to SARS-CoV-2 and to identify candidate neuroprotective drugs for COVID-19 patients. The susceptibility of hPSC-derived DA neurons to SARS-CoV-2 and the observed inflammatory and senescence transcriptional responses suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.
2021-10-20 | GSE174745 | GEO
Project description:COVID-19 patients commonly present with neurological signs of central nervous system (CNS) and/or peripheral nervous system dysfunction. However, which neural cells are permissive to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been controversial. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to SARS-CoV-2 infection, and that SARS-CoV-2 infection triggers a DA neuron inflammatory and cellular senescence response. A high-throughput screen in hPSC-derived DA neurons identified several FDA approved drugs, including riluzole, metformin, and imatinib, that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. RNA-seq analysis of human ventral midbrain tissue from COVID-19 patients, using formalin-fixed paraffin-embedded autopsy samples, confirmed the induction of an inflammatory and cellular senescence signature and identified low levels of SARS-CoV-2 transcripts. Our findings demonstrate that hPSC-derived DA neurons can serve as a disease model to study neuronal susceptibility to SARS-CoV-2 and to identify candidate neuroprotective drugs for COVID-19 patients. The susceptibility of hPSC-derived DA neurons to SARS-CoV-2 and the observed inflammatory and senescence transcriptional responses suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.
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2021-08-26 | GSE164784 | GEO
Project description:SARS-CoV-2 is an emerging coronavirus that causes dysfunctions in multiple human cells and tissues. Studies have looked at the entry of SARS-CoV-2 into host cells mediated by the viral spike protein and human receptor ACE2. However, less is known about the cellular immune responses triggered by SARS-CoV-2 viral proteins. Here, we show that the nucleocapsid of SARS-CoV-2 inhibits host pyroptosis by blocking Gasdermin D (GSDMD) cleavage. SARS-CoV-2-infected monocytes show enhanced cellular interleukin 1b (IL-1b) expression, but reduced IL-1b secretion. While SARS-CoV-2 infection promotes activation of the NLRP3 inflammasome and caspase-1, GSDMD cleavage and pyroptosis are inhibited in infected human monocytes. SARS-CoV-2 nucleocapsid protein associates with GSDMD in cells and inhibits GSDMD cleavage in vitro and in vivo. The nucleocapsid binds the GSDMD linker region and hinders GSDMD processing by caspase-1. These insights into how SARS-CoV-2 antagonizes cellular inflammatory responses may open new avenues for treating COVID-19 in the future.
| S-SCDT-EMBOJ-2021-108249 | biostudies-other