Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2

Nat Commun. 2022 Jan 20;13(1):405. doi: 10.1038/s41467-021-27893-2.

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of the coronavirus induced disease 2019 (COVID-19) with evolving variants of concern. It remains urgent to identify novel approaches against broad strains of SARS-CoV-2, which infect host cells via the entry receptor angiotensin-converting enzyme 2 (ACE2). Herein, we report an increase in circulating extracellular vesicles (EVs) that express ACE2 (evACE2) in plasma of COVID-19 patients, which levels are associated with severe pathogenesis. Importantly, evACE2 isolated from human plasma or cells neutralizes SARS-CoV-2 infection by competing with cellular ACE2. Compared to vesicle-free recombinant human ACE2 (rhACE2), evACE2 shows a 135-fold higher potency in blocking the binding of the viral spike protein RBD, and a 60- to 80-fold higher efficacy in preventing infections by both pseudotyped and authentic SARS-CoV-2. Consistently, evACE2 protects the hACE2 transgenic mice from SARS-CoV-2-induced lung injury and mortality. Furthermore, evACE2 inhibits the infection of SARS-CoV-2 variants (α, β, and δ) with equal or higher potency than for the wildtype strain, supporting a broad-spectrum antiviral mechanism of evACE2 for therapeutic development to block the infection of existing and future coronaviruses that use the ACE2 receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / immunology*
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • COVID-19 / blood
  • COVID-19 / epidemiology
  • COVID-19 / immunology*
  • Chlorocebus aethiops
  • Extracellular Vesicles / genetics
  • Extracellular Vesicles / immunology*
  • Extracellular Vesicles / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice, Transgenic
  • Neutralization Tests / methods
  • Pandemics / prevention & control
  • Protein Binding
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / immunology*
  • SARS-CoV-2 / metabolism
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology
  • Spike Glycoprotein, Coronavirus / metabolism
  • Survival Analysis
  • Vero Cells

Substances

  • Spike Glycoprotein, Coronavirus
  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • SARS-CoV-2 variants