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

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

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.