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Identification of A Drug Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colon Organoids

ABSTRACT: Identification of A Drug Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colon Organoids

PROVIDER: PRJNA622691 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11470655_1.fastq.gz	Fastqsanger.gz
	SRR11470655_2.fastq.gz	Fastqsanger.gz
	SRR11470656_1.fastq.gz	Fastqsanger.gz
	SRR11470656_2.fastq.gz	Fastqsanger.gz

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Identification of A Drug Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colon Organoids

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: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.

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