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

Cell Res. 2021 Aug;31(8):847-860. doi: 10.1038/s41422-021-00519-4. Epub 2021 Jun 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / metabolism*
  • Antiviral Agents / therapeutic use
  • Apoptosis
  • COVID-19 / complications
  • COVID-19 / drug therapy
  • COVID-19 / pathology*
  • COVID-19 / virology
  • Coronavirus Envelope Proteins / antagonists & inhibitors
  • Coronavirus Envelope Proteins / genetics
  • Coronavirus Envelope Proteins / metabolism*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Half-Life
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Respiratory Distress Syndrome / etiology*
  • SARS-CoV-2 / isolation & purification
  • SARS-CoV-2 / metabolism*
  • SARS-CoV-2 / pathogenicity
  • Spleen / metabolism
  • Spleen / pathology
  • Viral Load
  • Virulence

Substances

  • Antiviral Agents
  • Coronavirus Envelope Proteins
  • Cytokines
  • envelope protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2