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Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry.
J Virol. 2020 02 14; 94(5)JV

Abstract

Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that MAb binds to the virus surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, MAb binds to cell surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized MAb dosages in viral-receptor-dependent, Fc-receptor-dependent, and both-receptors-dependent viral entry pathways, delineating guidelines on MAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.IMPORTANCE Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.

Authors+Show Affiliations

Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA.Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA.Laboratory of Infection and Immunity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA.Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China.Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA.Laboratory of Infection and Immunity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.Laboratory of Infection and Immunity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA.Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China.Laboratory of Infection and Immunity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA LDu@nybc.org lifang@umn.edu.Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA LDu@nybc.org lifang@umn.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

31826992

Citation

Wan, Yushun, et al. "Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry." Journal of Virology, vol. 94, no. 5, 2020.
Wan Y, Shang J, Sun S, et al. Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J Virol. 2020;94(5).
Wan, Y., Shang, J., Sun, S., Tai, W., Chen, J., Geng, Q., He, L., Chen, Y., Wu, J., Shi, Z., Zhou, Y., Du, L., & Li, F. (2020). Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. Journal of Virology, 94(5). https://doi.org/10.1128/JVI.02015-19
Wan Y, et al. Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J Virol. 2020 02 14;94(5) PubMed PMID: 31826992.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. AU - Wan,Yushun, AU - Shang,Jian, AU - Sun,Shihui, AU - Tai,Wanbo, AU - Chen,Jing, AU - Geng,Qibin, AU - He,Lei, AU - Chen,Yuehong, AU - Wu,Jianming, AU - Shi,Zhengli, AU - Zhou,Yusen, AU - Du,Lanying, AU - Li,Fang, Y1 - 2020/02/14/ PY - 2019/11/27/received PY - 2019/12/04/accepted PY - 2019/12/13/pubmed PY - 2020/3/19/medline PY - 2019/12/13/entrez KW - IgG Fc receptor KW - MERS coronavirus KW - SARS coronavirus KW - antibody-dependent enhancement of viral entry KW - neutralizing antibody KW - spike protein KW - viral receptor JF - Journal of virology JO - J Virol VL - 94 IS - 5 N2 - Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that MAb binds to the virus surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, MAb binds to cell surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized MAb dosages in viral-receptor-dependent, Fc-receptor-dependent, and both-receptors-dependent viral entry pathways, delineating guidelines on MAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.IMPORTANCE Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/31826992/full_citation L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31826992/ DB - PRIME DP - Unbound Medicine ER -