Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection

doi:10.1007/s13238-020-00811-w

Protein Cell

2021, Vol. 12

Issue (9) : 717-733 https://doi.org/10.1007/s13238-020-00811-w

RESEARCH ARTICLE

Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection

Rongjuan Pei², Jianqi Feng¹, Yecheng Zhang², Hao Sun², Lian Li¹, Xuejie Yang^5,⁷, Jiangping He^5,⁶, Shuqi Xiao², Jin Xiong², Ying Lin¹, Kun Wen⁸, Hongwei Zhou⁸, Jiekai Chen^5,^6,⁷, Zhili Rong^1,^3,⁴(

), Xinwen Chen^2,⁵(

)

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 Health-Guangdong 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

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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

Corresponding Author(s): Zhili Rong,Xinwen Chen

Online First Date: 11 January 2021 Issue Date: 14 October 2021

Cite this article:

Rongjuan Pei,Jianqi Feng,Yecheng Zhang, et al. Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection[J]. Protein Cell, 2021, 12(9): 717-733.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-020-00811-w
https://academic.hep.com.cn/pac/EN/Y2021/V12/I9/717

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