Jianqi Feng
Yecheng Zhang
Hao Sun
Lian Li
Xuejie Yang
Jiangping He
Shuqi Xiao
Jin Xiong
Ying Lin
Kun Wen
Hongwei Zhou
Jiekai Chen
Zhili Rong
Xinwen Chen
1 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China;
2 Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
3 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China;
4 Dermatology Hospital, Southern Medical University, Guangzhou 510091, China;
5 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;
6 The Centre of Cell Lineage and Atlas (CCLA), Bioland Laboratory (Guangzhou Regenerative Medicine and HealthGuangdong Laboratory), Guangzhou 510530, China;
7 Joint School of Life Sciences, Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 511436, China;
8 Microbiome Medicine Center, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
Funds: We thank Prof. Mengfeng Li from Southern Medical University and Bo Li from Sun Yat-sen University for helpful discussion. We are particularly grateful to Tao Du, Lun Wang and the running team from Zhengdian Biosafety Level 3 Laboratory, to Pei Zhang and Anna Du from the core facility of Wuhan Institute of Virology for technical support for TEM experiment. We thank Prof. Zhengli Shi from Wuhan Institute of Virology for providing the rabbit antibody against viral N protein. We thank Prof. Jinghua Yan from Institute of Microbiology, Chinese Academy of Sciences for providing CB6 antibody. This work was supported by grants from National Natural Science Foundation of China (Grant Nos. 82070002, 82072329, 81872511, and 81670093), Frontier Research Program of Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) (2018GZR110105005), National Science and Technology Major Project (2018ZX10301101), the Natural Science Foundation of Guangdong Province (2018A030313455), the Program of Department of Science and Technology of Guangdong Province (2014B020212018), National Key Research and Development Project (2018YFA0507201), the special project for COVID-19 of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2020GZR110106006), the emergency grants for prevention and control of SARS-CoV-2 of Guangdong province (2020B111108001) and National Postdoctoral Program for Innovative Talent (BX20190089).
Accepted Date:2021-01-27
Abstract
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived selforganized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.Keywords: COVID-19,
SARS-CoV-2,
lung organoids,
cell tropism,
cellular metabolism,
drug discovery
PDF全文下载地址:
http://www.protein-cell.org/article/exportPdf?id=5bf65c66-f73c-4b22-aeec-c297578ffb48&language=en
