Hartman Institute for Therapeutic Organ Regeneration

A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection.

TitleA multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection.
Publication TypeJournal Article
Year of Publication2023
AuthorsTang X, Xue D, Zhang T, Nilsson-Payant BE, Carrau L, Duan X, Gordillo M, Tan AY, Qiu Y, Xiang J, Schwartz RE, tenOever BR, Evans T, Chen S
JournalNat Cell Biol
Volume25
Issue3
Pagination381-389
Date Published2023 Mar
ISSN1476-4679
KeywordsCircadian Rhythm Signaling Peptides and Proteins, COVID-19, Humans, Lung, Organoids, RNA, SARS-CoV-2
Abstract

<p>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 screens. 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.</p>

DOI10.1038/s41556-023-01095-y
Alternate JournalNat Cell Biol
PubMed ID36918693
PubMed Central IDPMC10014579
Grant ListU01 DK127777 / DK / NIDDK NIH HHS / United States

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Hartman Institute for Therapeutic Organ Regeneration
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