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.
【저자키워드】 Molecular biology, cell death, 【초록키워드】 SARS-CoV-2, Inflammation, ARDS, Cytokine storm, Mutation, Cytokines, macrophages, acute respiratory distress syndrome, lung, cytokine, chemokines, in vitro, Prophylactic, chemokine, activity, Protein, Viral, heterologous expression, Viral load, mice, Lungs, therapeutic, death, drug target, in vivo, cell death, inhibitor, spleen, Protective, Human angiotensin-converting enzyme 2, acute respiratory distress, Anti-SARS-CoV-2 Activity, administration, angiotensin, cell types, respiratory distress, cation channels, Intravenous administration, Support, infected cells, secretion, syndrome, human Angiotensin-converting enzyme, transgenic mice, multi-organ failure, SARS-CoV-2-infected cells, damages, membranes, SARS-CoV-2 envelope, Cell, robust, caused, reduced, exhibited, cause, expressing, purified, susceptible cell, dominant negative, channel inhibitor, positively correlated, the SARS-CoV-2, 【제목키워드】 Protein, antiviral target, acute respiratory distress, respiratory distress, syndrome, cause,