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

Lamiaa El-Shennawy; Andrew D. Hoffmann; Nurmaa Khund Dashzeveg; Kathleen M. McAndrews; Paul J. Mehl; Daphne Cornish; Zihao Yu; Valerie L. Tokars; Vlad Nicolaescu; Anastasia Tomatsidou; Chengsheng Mao; Christopher J. Felicelli; Chia Feng Tsai; Carolina Ostiguin; Yuzhi Jia; Lin Li; Kevin Furlong; Jan Wysocki; Xin Luo; Carolina F. Ruivo; Daniel Batlle; Thomas J. Hope; Yang Shen; Young Kwang Chae; Hui Zhang; Valerie S. LeBleu; Tujin Shi; Suchitra Swaminathan; Yuan Luo; Dominique Missiakas; Glenn C. Randall; Alexis R. Demonbreun; Michael G. Ison; Raghu Kalluri; Deyu Fang; Huiping Liu

doi:10.1038/s41467-021-27893-2

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

Lamiaa El-Shennawy, Andrew D. Hoffmann, Nurmaa Khund Dashzeveg, Kathleen M. McAndrews, Paul J. Mehl, Daphne Cornish, Zihao Yu, Valerie L. Tokars, Vlad Nicolaescu, Anastasia Tomatsidou, Chengsheng Mao, Christopher J. Felicelli, Chia Feng Tsai, Carolina Ostiguin, Yuzhi Jia, Lin Li, Kevin Furlong, Jan Wysocki, Xin Luo, Carolina F. RuivoDaniel Batlle, Thomas J. Hope, Yang Shen, Young Kwang Chae, Hui Zhang, Valerie S. LeBleu, Tujin Shi, Suchitra Swaminathan, Yuan Luo, Dominique Missiakas, Glenn C. Randall, Alexis R. Demonbreun, Michael G. Ison, Raghu Kalluri, Deyu Fang, Huiping Liu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

112 Scopus citations

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.

Original language	English (US)
Article number	405
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27893-2
State	Published - Dec 2022

Funding

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.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-27893-2

Cite this

El-Shennawy, L., Hoffmann, A. D., Dashzeveg, N. K., McAndrews, K. M., Mehl, P. J., Cornish, D., Yu, Z., Tokars, V. L., Nicolaescu, V., Tomatsidou, A., Mao, C., Felicelli, C. J., Tsai, C. F., Ostiguin, C., Jia, Y., Li, L., Furlong, K., Wysocki, J., Luo, X., ... Liu, H. (2022). Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2. Nature communications, 13(1), Article 405. https://doi.org/10.1038/s41467-021-27893-2

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title = "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.",

author = "Lamiaa El-Shennawy and Hoffmann, {Andrew D.} and Dashzeveg, {Nurmaa Khund} and McAndrews, {Kathleen M.} and Mehl, {Paul J.} and Daphne Cornish and Zihao Yu and Tokars, {Valerie L.} and Vlad Nicolaescu and Anastasia Tomatsidou and Chengsheng Mao and Felicelli, {Christopher J.} and Tsai, {Chia Feng} and Carolina Ostiguin and Yuzhi Jia and Lin Li and Kevin Furlong and Jan Wysocki and Xin Luo and Ruivo, {Carolina F.} and Daniel Batlle and Hope, {Thomas J.} and Yang Shen and Chae, {Young Kwang} and Hui Zhang and LeBleu, {Valerie S.} and Tujin Shi and Suchitra Swaminathan and Yuan Luo and Dominique Missiakas and Randall, {Glenn C.} and Demonbreun, {Alexis R.} and Ison, {Michael G.} and Raghu Kalluri and Deyu Fang and Huiping Liu",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-021-27893-2",

language = "English (US)",

volume = "13",

journal = "Nature communications",

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El-Shennawy, L, Hoffmann, AD, Dashzeveg, NK, McAndrews, KM, Mehl, PJ, Cornish, D, Yu, Z, Tokars, VL, Nicolaescu, V, Tomatsidou, A, Mao, C, Felicelli, CJ, Tsai, CF, Ostiguin, C, Jia, Y, Li, L, Furlong, K, Wysocki, J, Luo, X, Ruivo, CF, Batlle, D , Hope, TJ, Shen, Y, Chae, YK, Zhang, H, LeBleu, VS, Shi, T, Swaminathan, S , Luo, Y, Missiakas, D, Randall, GC, Demonbreun, AR, Ison, MG, Kalluri, R, Fang, D & Liu, H 2022, 'Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2', Nature communications, vol. 13, no. 1, 405. https://doi.org/10.1038/s41467-021-27893-2

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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

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.

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

Abstract

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UN SDGs

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