๐ Molecular mechanism for antibody-dependent enhancement of coronavirus entry
Copyright ยฉ 2020 American Society for Microbiology. 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.
keywords
๐ cells expressing (60)
๐ spike protein (353)
๐ receptor-binding domain (99)
๐ host cell (262)
๐ cell surface (110)
๐ data suggest (146)
๐ respiratory syndrome (2004)
๐ viral entry (91)
author
๐ค Wan, Yushun
๐ค Shang, Jian
๐ค Sun, Shihui
๐ค Tai, Wanbo
๐ค Chen, Jing
๐ค Geng, Qibin
๐ค He, Lei
๐ค Chen, Yuehong
๐ค Wu, Jianming
๐ค Shi, Zhengli
๐ค Zhou, Yusen
๐ค Du, Lanying
๐ค Li, Fang
year
โฐ 2020
journal
๐ Journal of Virology
issn
๐ 10985514 0022538X
volume
94
number
5
page
citedbycount
0
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