Abstract
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.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic
Intensive studies on host–pathogen interactions have partially unveiled the immunopathogenesis of COVID-19.6–8 Similar to two other beta-coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), which could cause fatal pneumonia,[9,10,11] SARS-CoV-2 can induce secretion of inflammatory cytokines and cell death by releasing pathogen-associated molecular patterns (PAMPs), such as viral RNA and damage-associated molecular patterns (DAMPs), including Adenosine triphosphate (ATP) and DeoxyriboNucleic Acid (DNA)
SARS-CoV-2 envelope (2-E) forms a cation channel Potential electric signals mediated by 2-E proteins were assessed using the planar lipid bilayer recording technique (Supplementary information, Fig. S1a, b)
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic. It is very likely that SARS-CoV-2 may antagonize interferon responses in various interferon signaling pathways according to studies on SARS-CoV.[2,12,13,14] in addition to the dysfunctional defensive responses of host cells and the Received: 15 February 2021 Accepted: 13 May 2021 Published online: 10 June 2021 antagonism of the interferon signaling pathways by the virus, it remains unknown whether the SARS-CoV-2 itself possesses an offensive virulence factor that can induce cytokine storm and kill targeted cells in a direct and rapid manner
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