TY - JOUR
T1 - Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2
AU - El-Shennawy, Lamiaa
AU - Hoffmann, Andrew D.
AU - Dashzeveg, Nurmaa Khund
AU - McAndrews, Kathleen M.
AU - Mehl, Paul J.
AU - Cornish, Daphne
AU - Yu, Zihao
AU - Tokars, Valerie L.
AU - Nicolaescu, Vlad
AU - Tomatsidou, Anastasia
AU - Mao, Chengsheng
AU - Felicelli, Christopher J.
AU - Tsai, Chia Feng
AU - Ostiguin, Carolina
AU - Jia, Yuzhi
AU - Li, Lin
AU - Furlong, Kevin
AU - Wysocki, Jan
AU - Luo, Xin
AU - Ruivo, Carolina F.
AU - Batlle, Daniel
AU - Hope, Thomas J.
AU - Shen, Yang
AU - Chae, Young Kwang
AU - Zhang, Hui
AU - LeBleu, Valerie S.
AU - Shi, Tujin
AU - Swaminathan, Suchitra
AU - Luo, Yuan
AU - Missiakas, Dominique
AU - Randall, Glenn C.
AU - Demonbreun, Alexis R.
AU - Ison, Michael G.
AU - Kalluri, Raghu
AU - Fang, Deyu
AU - Liu, Huiping
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85123197980
UR - https://www.scopus.com/pages/publications/85123197980#tab=citedBy
U2 - 10.1038/s41467-021-27893-2
DO - 10.1038/s41467-021-27893-2
M3 - Article
C2 - 35058437
AN - SCOPUS:85123197980
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 405
ER -