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

• Published in: Cell research Vol. 31; no. 8; pp. 847 - 860
• Main Authors: Xia, Bingqing, Shen, Xurui, He, Yang, Pan, Xiaoyan, Liu, Feng-Liang, Wang, Yi, Yang, Feipu, Fang, Sui, Wu, Yan, Duan, Zilei, Zuo, Xiaoli, Xie, Zhuqing, Jiang, Xiangrui, Xu, Ling, Chi, Hao, Li, Shuangqu, Meng, Qian, Zhou, Hu, Zhou, Yubo, Cheng, Xi, Xin, Xiaoming, Jin, Lin, Zhang, Hai-Lin, Yu, Dan-Dan, Li, Ming-Hua, Feng, Xiao-Li, Chen, Jiekai, Jiang, Hualiang, Xiao, Gengfu, Zheng, Yong-Tang, Zhang, Lei-Ke, Shen, Jingshan, Li, Jia, Gao, Zhaobing
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.08.2021; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/21; 13/31; 13/44; 13/51; 14; 14/19; 38/1; 38/77; 631/337; 631/80/82; 64/110; 64/60; 82/1; 82/58; 82/83; ACE2; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Animals; Antiviral Agents - chemistry; Antiviral Agents - metabolism; Antiviral Agents - therapeutic use; Apoptosis; Biomedical and Life Sciences; Cell Biology; Cell death; Channel gating; Chemokines; Coronavirus Envelope Proteins - antagonists & inhibitors; Coronavirus Envelope Proteins - genetics; Coronavirus Envelope Proteins - metabolism; COVID-19; COVID-19 - complications; COVID-19 - pathology; COVID-19 - virology; COVID-19 Drug Treatment; Cytokine storm; Cytokines; Cytokines - metabolism; Disease Models, Animal; Half-Life; Humans; Inflammation; Intravenous administration; Ion channels; Life Sciences; Lipid membranes; Lipids; Lung - metabolism; Lung - pathology; Lungs; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mortality; Mutagenesis, Site-Directed; Mutation; Peptidyl-dipeptidase A; pH effects; Proteins; Respiratory distress syndrome; Respiratory Distress Syndrome - etiology; SARS-CoV-2 - isolation & purification; SARS-CoV-2 - metabolism; SARS-CoV-2 - pathogenicity; Severe acute respiratory syndrome coronavirus 2; Spleen; Spleen - metabolism; Spleen - pathology; Storm damage; Therapeutic targets; Transgenic mice; Viral envelope proteins; Viral Load; Virulence
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/s41422-021-00519-4

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.