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

SUBMITTER: El-Shennawy L

PROVIDER: S-EPMC8776790 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

El-Shennawy Lamiaa L Hoffmann Andrew D AD Dashzeveg Nurmaa Khund NK McAndrews Kathleen M KM Mehl Paul J PJ Cornish Daphne D Yu Zihao Z Tokars Valerie L VL Nicolaescu Vlad V Tomatsidou Anastasia A Mao Chengsheng C Felicelli Christopher J CJ Tsai Chia-Feng CF Ostiguin Carolina C Jia Yuzhi Y Li Lin L Furlong Kevin K Wysocki Jan J Luo Xin X Ruivo Carolina F CF Batlle Daniel D Hope Thomas J TJ Shen Yang Y Chae Young Kwang YK Zhang Hui H LeBleu Valerie S VS Shi Tujin T Swaminathan Suchitra S Luo Yuan Y Missiakas Dominique D Randall Glenn C GC Demonbreun Alexis R AR Ison Michael G MG Kalluri Raghu R Fang Deyu D Liu Huiping H

Nature communications 20220120 1

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 asso ...[more]

PMID: 35058437

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Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)has caused the pandemic of the coronavirus induced disease 2019 (COVID-19) with 216 million cases and 4.5 million deathsas of September 2021.Thathas been exacerbated by mutated variants such as α, β, and with high infection rates and increased breakthroughs,resulting in vaccine inefficiencies and resistance to therapeutic monoclonal antibodies. Itremains urgentto identify novel therapeutics against broad strains of SARS-CoV-2 andfuture emerging corona viruses to protect the immune-compromised, unvaccinated, and even vaccinatedalikefrom evolvinginfectious diseases. Onebig question is whether we can harness power from human antiviral immunity for such broad therapeutic development. Wild-type SARS-CoV-2 and its variants infect human and other host cellsvia the entry receptor angiotensin-converting enzyme 2 (ACE2),triggeringinnate and adaptive immune responses. Herein, we reportan increase in circulating extracellular vesicles (EVs) that express ACE2(evACE2)in plasma ofboth acuteand convalescent COVID-19 patientsas part of innate antiviral responseassociatedwith severe pathogenesis. Furthermore, evACE2 isolated from both human plasma and engineered EV-producing cell lines neutralizes SARS-CoV-2 infection by competingwith cellular ACE2.Notably,evACE2 blocksthe binding of the viral spike (S)protein RBD to ACE2+cells ata135-fold higherpotencythan vesicle-free recombinant human ACE2 (rhACE2). Furthermore, evACE2 preventscellinfections by both pseudotyped and authentic SARS-CoV-2at a 60-to 80-fold higher efficacy than rhACE2; and itprotectsthe hACE2 mice from SARS-CoV-2-induced lung injury and mortality. More importantly, evACE2 inhibitsthe infection of SARS-CoV-2 variants (α, β,and δ)with an equal or even higherpotencythan forthe WT strain, supportingevACE2 as a broad-spectrum antiviral mechanismfor therapeutic developmentto block the infection of existing and future coronaviruses that use ACE2 as a receptor.

Dataset Information

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

Publications

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

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