Molecular mechanism for antibody-dependent enhancement of coronavirus entry

Yushun Wan, Jian Shang, Shihui Sun, Wanbo Tai, Jing Chen, Qibin Geng, Lei He, Yuehong Chen, Jianming Wu, Zhengli Shi, Yusen Zhou, Lanying Du, Fang Li

Research output: Contribution to journalArticle

115 Scopus citations

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.

Original languageEnglish (US)
Article numbere02015-19
JournalJournal of virology
Volume94
Issue number5
DOIs
StatePublished - Mar 1 2020

Keywords

  • Antibody-dependent enhancement of viral entry
  • Antibody-dependent enhancement of viral entry
  • IgG Fc receptor
  • MERS coronavirus
  • Neutralizing antibody
  • SARS coronavirus
  • Spike protein
  • Viral receptor

PubMed: MeSH publication types

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

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  • Cite this

    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), [e02015-19]. https://doi.org/10.1128/JVI.02015-19