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 - Funding Information:
We are thankful to the team of Northwestern COVID-19 Antibody and Cancer Collaborative Group and advisory members, especially Drs. Alfred L. George Jr. (who also edited our manuscript), Judith Varner, Richard D’Aquila, Leonidas C. Platanias, Rex L. Chishom, Alan R. Hauser, Elizabeth M. McNally, and William A. Muller for their scientific input and resourceful support for the project. The work was partially funded by Chicago Biomedical Consortium Accelerator Award A-017 (H.L. and D.F.), the United States National Cancer Institute 1F32CA257345-01 (L.E.), Northwestern University Feinberg School of Medicine Emerging and Re-emerging Pathogens Program (EREPP) (H.L.), Department of Pharmacology Start-up fund (H.L.), the R.H. Lurie Comprehensive Cancer Center Support Grant NIH/NCI CA060553 (S.W.) and Blood Biobank fund (M.I.), and Lyda Hill Philanthropies® (R.K.). We gratefully acknowledge the support from the R.H. Lurie Comprehensive Cancer Center Structural Biology Facility and Flow Core. Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system, through support of NIH 1S10OD011996-01. The Ametek K3 DDE at Northwestern University for cryo-EM was generously provided by Professor Robert A. Lamb, Ph.D., Sc.D., HHMI investigator. The ACE2-expressing HeLa cells were provided by Dr. Thomas Gallagher of Stritch Medical School, Loyola University. We appreciate the effort of BSL-3 facility at the NIAID-supported University of Chicago Howard T. Ricketts Regional Biochontainment Laboratory for performing the wild-type and variant SARS-CoV-2 live virus study.
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 - http://www.scopus.com/inward/record.url?scp=85123197980&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123197980&partnerID=8YFLogxK
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 -