Molecular #mechanism for #ADE of #coronavirus entry (J Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Virol. 2019 Dec 11. pii: JVI.02015-19. doi: 10.1128/JVI.02015-19. [Epub ahead of print]

Molecular mechanism for antibody-dependent enhancement of coronavirus entry.

Wan Y1, Shang J1, Sun S, Tai W2, Chen J3, Geng Q1, He L4, Chen Y4, Wu J1, Shi Z3, Zhou Y, Du L5, Li F6.

Author information: 1 Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA. 2 Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA. 3 Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China. 4 Laboratory of infection and immunity, Beijing Institute of Microbiology and Epidemiology, Beijing, China. 5 Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA lifang@umn.edu LDu@nybc.org. 6 Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA lifang@umn.edu LDu@nybc.org.

 

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 host cell surface and then fusing viral and host membranes. Here we investigated how a neutralizing monoclonal antibody (mAb), which targets the receptor-binding domain (RBD) of 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, antibody-dependent, and both-receptors-dependent 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.

 

Significance

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 sub-neutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the virus-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.

Copyright © 2019 American Society for Microbiology.

PMID: 31826992 DOI: 10.1128/JVI.02015-19

Keywords: Coronavirus; MERS-CoV; Monoclonal antibodies; ADE.

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Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.