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.

细胞因子风暴和多器官衰竭是 SARS-CoV-2 相关死亡的主要原因。然而，SARS-CoV-2 造成的过度损害的根源仍然很大程度上未知。在这里，我们表明，单独的 SARS-CoV-2 包膜 (2-E) 蛋白就能够在体外和体内引起急性呼吸窘迫综合征 (ARDS) 样损伤。 2-E 蛋白被发现在双层脂膜中形成一种 pH 敏感的阳离子通道。正如在 SARS-CoV-2 感染的细胞中观察到的，2-E 通道的异源表达诱导各种易感细胞类型的快速细胞死亡，以及巨噬细胞中细胞因子和趋化因子的大量分泌。给小鼠静脉注射纯化的 2-E 蛋白会导致肺和脾脏出现类似 ARDS 的病理损伤。降低 2-E 通道活性的显性失活突变会减弱细胞死亡和 SARS-CoV-2 的产生。新发现的通道抑制剂在体外表现出有效的抗 SARS-CoV-2 活性和优异的细胞保护活性，并且这些活性与 2-E 通道的抑制呈正相关。重要的是，预防性和治疗性给予通道抑制剂可有效减少表达人血管紧张素转换酶 2 (hACE-2) 的 SARS-CoV-2 感染转基因小鼠肺部的病毒载量和炎症细胞因子的分泌。我们的研究表明 2-E 是一种有前景的抗 SARS-CoV-2 药物靶点。