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.
Highlights
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
Our studies have defined evACE2 as an innovative decoy therapeutic that efficiently blocks the infectious diseases caused by SARS-CoV-2 and its variants of concern, and presumably all future emerging coronaviruses that utilize angiotensin-converting enzyme 2 (ACE2) as their initial tethering receptor
EvACE2 inhibits SARS-CoV-2 infection by competing with host cell surface ACE2, which has been speculated in a recent study showing that recombinant human ACE2 (rhACE2) inhibits SARS-CoV-2 infection[26,29] and ACE2-containing extracellular vesicles (EVs) bind to SARS-CoV-2 spike protein[58,59]
Summary
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). 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. To better protect vulnerable people, both unvaccinated and vaccinated, it is urgent to develop novel therapeutics that can broadly target distinct strains of evolving SARS-CoV-2 and future coronaviruses. COVID-19 patients have reportedly been used to treat active infection of SARS-CoV-2 or severe diseases[34,35], we aimed to identify previously unknown anti-viral components from the human plasma that may inform on potential new therapeutics
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