02569nas a2200337   4500000000100000000000100001008004100002260001200043653002500055653001500080100001600095700001800111700001400129700003100143700001700174700001700191700002000208700001800228700001600246700001600262700002300278700002500301700001500326700001800341245008800359856005500447300001200502490000700514520169600521022001402217       2023                            d  c2023-0310aEmbryonic stem cells10aSARS-CoV-21 aXuming Tang1 aDongxiang Xue1 aTuo Zhang1 aBenjamin E. Nilsson-Payant1 aLucia Carrau1 aXiaohua Duan1 aMiriam Gordillo1 aAdrian Y. Tan1 aYunping Qiu1 aJenny Xiang1 aRobert E. Schwartz1 aBenjamin R. tenOever1 aTodd Evans1 aShuibing Chen00aA multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection  uhttps://www.nature.com/articles/s41556-023-01095-y  a381-3890 v253 aCOVID-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.  a1476-4679