A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection
Abstract
COVID-19 is a systemic disease involving multiple organs. We previously established a platform to derive organoids and cells from human pluripotent stem cells to model SARS-CoV-2 infection and perform drug screens1,2. This provided insight into cellular tropism and the 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 multiplicities of infection for lung airway organoids, lung alveolar organoids and cardiomyocytes, and identified several genes that are generally implicated in controlling SARS-CoV-2 infection, including CIART, the circadian-associated repressor of transcription. Lung airway organoids, lung alveolar organoids and cardiomyocytes derived from isogenic CIART−/− human pluripotent stem cells were significantly resistant to SARS-CoV-2 infection, independently of viral entry. Single-cell RNA-sequencing analysis further validated the decreased levels of SARS-CoV-2 infection in ciliated-like cells of lung airway organoids. CUT&RUN, ATAC-seq and RNA-sequencing analyses showed that CIART controls SARS-CoV-2 infection at least in part through the regulation of NR4A1, a gene also identified from the multi-organoid analysis. Finally, transcriptional profiling and pharmacological inhibition led to the discovery that the Retinoid X Receptor pathway regulates SARS-CoV-2 infection downstream of CIART and NR4A1. The multi-organoid platform identified the role of circadian-clock regulation in SARS-CoV-2 infection, which provides potential therapeutic targets for protection against COVID-19 across organ systems.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2023
- Source ID
- 10.1038/s41556-023-01095-y
Entities
People
- Adrian Y. Tan
- Benjamin E. Nilsson-payant
- Benjamin R tenOever
- Dongxiang Xue
- Jenny Xiang
- Lucia Carrau
- Miriam Gordillo
- Robert E. Schwartz
- Shuibing Chen
- Todd Evans
- Tuo Zhang
- Xiaohua Duan
- Xuming Tang
- Yunping Qiu
Organizations
- Gates Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases
- United States Department of Defense