@article{2096,
  keywords = {Embryonic stem cells, SARS-CoV-2},
  author = {Xuming Tang and Dongxiang Xue and Tuo Zhang and Benjamin E. Nilsson-Payant and Lucia Carrau and Xiaohua Duan and Miriam Gordillo and Adrian Y. Tan and Yunping Qiu and Jenny Xiang and Robert E. Schwartz and Benjamin R. tenOever and Todd Evans and Shuibing Chen},
  title = {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.},
  year = {2023},
  journal = {Nature Cell Biology},
  volume = {25},
  pages = {381-389},
  month = {2023-03},
  issn = {1476-4679},
  url = {https://www.nature.com/articles/s41556-023-01095-y},
  doi = {10.1038/s41556-023-01095-y},
  language = {en},
}