A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection.
A multi-organoid platform identifies CIART as a key factor for SARS-CoV-2 infection.
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DOI：
10.1038/s41556-023-01095-y
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发表时间：
2023-03
影响因子：
21.3
通讯作者：
Chen, Shuibing
中科院分区：
文献类型：
--
作者：
Tang, Xuming;Xue, Dongxiang;Zhang, Tuo;Nilsson-Payant, Benjamin E. E.;Carrau, Lucia;Duan, Xiaohua;Gordillo, Miriam;Tan, Adrian Y. Y.;Qiu, Yunping;Xiang, Jenny;Schwartz, Robert E. E.;tenOever, Benjamin R. R.;Evans, Todd;Chen, Shuibing
COVID-19是一种累及多器官的全身性疾病。我们之前建立了一个平台，从人类多能干细胞中提取类器官和细胞，以模拟SARS-CoV-2感染并进行药物筛选。这提供了对细胞趋向性和宿主反应的深入了解，但调节SARS-CoV-2感染的分子机制仍然不明确。在这里，我们系统地研究了SARS-CoV-2感染在不同感染多样性下引起的肺气道类器官、肺泡类器官和心肌细胞转录谱的变化，并确定了几个通常与控制SARS-CoV-2感染有关的基因，包括CIART（昼夜节律相关的转录抑制因子）。来自等基因CIART - / -人多能干细胞的肺气道类器官、肺泡类器官和心肌细胞对SARS-CoV-2感染具有显著的抗性，与病毒的侵入无关。单细胞rna测序分析进一步证实了肺气道类器官纤毛样细胞中SARS-CoV-2感染水平的降低。CUT&RUN、ATAC-seq和rna测序分析表明，CIART至少在一定程度上通过调控NR4A1来控制SARS-CoV-2感染，NR4A1也是多器官分析中发现的一个基因。最后，转录谱分析和药理学抑制使我们发现类视黄醇X受体途径调节CIART和NR4A1下游的SARS-CoV-2感染。多器官平台确定了生物钟调节在SARS-CoV-2感染中的作用，这为跨器官系统保护COVID-19提供了潜在的治疗靶点。人多器官系统的系统性感染表明，宿主因子CIART的缺乏通过下调RXR通路和随后的脂肪酸合成损伤来损害SARS-CoV-2感染。
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. Systematic infection of a human multi-organoid system shows that deficiency in the host factor CIART impairs SARS-CoV-2 infection through downregulation of the RXR pathway and subsequent impairment of fatty-acid synthesis.
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DOI：
10.1093/bioinformatics/btx346
发表时间：
2017-10-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gel B;Serra E
通讯作者：
Serra E
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
7.3
作者：
Huff S;Kummetha IR;Tiwari SK;Huante MB;Clark AE;Wang S;Bray W;Smith D;Carlin AF;Endsley M;Rana TM
通讯作者：
Rana TM
影响因子：
4.8
作者：
Annayev, Yunus;Adar, Sheera;Ye, Rui
通讯作者：
Ye, Rui
SARS-CoV-2感染后人体气道和肺泡类器官的宿主代谢失调和细胞向性识别
影响因子：
21.1
作者：
Pei R;Feng J;Zhang Y;Sun H;Li L;Yang X;He J;Xiao S;Xiong J;Lin Y;Wen K;Zhou H;Chen J;Rong Z;Chen X
通讯作者：
Chen X