Volume 31, No 8, Aug 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 8, August 2021: 847-860   |  Open Access

ORIGINAL ARTICLES

SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target

Bingqing Xia^1,2 , Xurui Shen^1,2 , Yang He^1,2 , Xiaoyan Pan³ , Feng-Liang Liu⁴ , Yi Wang^1,2 , Feipu Yang^1,2 , Sui Fang¹ , Yan Wu³ , Zilei Duan⁴ , Xiaoli Zuo¹ , Zhuqing Xie^1,5 , Xiangrui Jiang^1,2 , Ling Xu⁴ , Hao Chi^1,2 , Shuangqu Li^1,2 , Qian Meng¹ , Hu Zhou^1,2 , Yubo Zhou^1,2 , Xi Cheng^1,2 , Xiaoming Xin⁵ , Lin Jin⁴ , Hai-Lin Zhang⁶ , Dan-Dan Yu⁴ , Ming-Hua Li⁷ , Xiao-Li Feng⁷ , Jiekai Chen^8,9,10 , Hualiang Jiang^1,2 , Gengfu Xiao³ , Yong-Tang Zheng^4,7,* , Lei-Ke Zhang^3,* , Jingshan Shen^1,2,* , Jia Li^1,2,11,* , Zhaobing Gao^1,2,11,12,*

¹CAS Key Laboratory of Receptor Research, Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
²University of Chinese Academy of Sciences, Beijing, China
³State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
⁴Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
⁵Shanghai University of Medicine & Health Sciences, Shanghai, China
⁶State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
⁷Kunming National High-level Biosafety Research Center for Non-human Primates, Center for Biosafety MegaScience, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
⁸Center for Cell Fate and Lineage (CCLA), Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, Guangdong, China
⁹CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China
¹⁰Joint School of Life Science, Guangzhou Medical University, Guangzhou, Guangdong, China
¹¹Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, Guangdong, China
¹²School of Pharmacy, Fudan University, Shanghai, China
These authors contributed equally: Bingqing Xia, Xurui Shen, Yang He, Xiaoyan Pan, Feng-Liang Liu Correspondence: Yong-Tang Zheng(zhengyt@mail.kiz.ac.cn)Lei-Ke Zhang(zhangleike@wh.iov.cn)Jingshan Shen(shenjingshan@simm.ac.cn)Jia Li(jli@simm.ac.cn)Zhaobing Gao(zbgao@simm.ac.cn)

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.

https://doi.org/10.1038/s41422-021-00519-4

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