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.