Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry
By Yushun Wan, J. Shang, Shihui Sun, Wanbo Tai, J. Chen, Q. Geng, Lei He, Yuehong Chen, Jianming Wu, Zhènglì Shí and 3 more. Journal of Virology, 2019
637 citations recorded by the source corpus.
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. 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.
Subfields: Animal Science and Zoology, Infectious Diseases
View Paper: https://www.semanticscholar.org/paper/5e8604a8827af0753d6c757a737ba7a3897e2d52
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In Infectious Diseases
Citations in the corpus
- Immune Response, Inflammation, and the Clinical Spectrum of COVID-19 (2020, background): “Thus, IgG anti-S antibodies bound to FcγRII on mononuclear phagocyte membranes enhance viral entrance through canonical viral-receptor pathways, as recently shown for MERS-CoV (90), thereby activating these cells and inducing the production of proinflammatory cytokines.”
- Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus (2020, positive): “Some antibodies against SARSCoV-1 Spike mediate antibody-dependent enhancement (ADE) of infection in vitro and exacerbate disease in animal models (Jaume et al., 2011; Wan et al., 2020; Wang et al., 2014; Yip et al., 2016).”
- A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS (2020, background): “However, because antibody-dependent enhancement (ADE) has been reported for CoV immune response (Corapi et al., 1992; Hohdatsu et al., 1998; Jaume et al., 2011; Kam et al., 2007; Vennema et al., 1990; Wan et al., 2020; Wang et al., 2014), minimized effective immunogens are sought.”
- Deployment of convalescent plasma for the prevention and treatment of COVID-19. (2020, positive): “Concerns about coronavirus-ADE stem primarily from in vitro studies using mAbs, whose relevance is uncertain to the polyclonal antibody composition found in convalescent plasma (41).”
- Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity (2020, positive): “surface proteins could increase the risk of severe disease due to antibody-dependent enhancement (ADE), as has been observed for SARS-CoV (16, 17).”
- Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike (2020, positive): “Moreover, it has been reported (Wan et al., 2019) that antibody mediated enhancement occurs via antibodies that mimic receptor attachment whereas CR3022-like binding might circumvent this by pre-attachment conversion to the post-fusion state.”