Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus.

Autor: Adams C; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Carbaugh DL; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Shu B; Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore.; Centre for Bio-Imaging Sciences, Department of Biological Sciences, National University of Singapore, Singapore, Singapore., Ng TS; Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore.; Centre for Bio-Imaging Sciences, Department of Biological Sciences, National University of Singapore, Singapore, Singapore., Castillo IN; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Bhowmik R; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Segovia-Chumbez B; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Puhl AC; Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America., Graham S; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Diehl SA; Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America., Lazear HM; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Lok SM; Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, Singapore.; Centre for Bio-Imaging Sciences, Department of Biological Sciences, National University of Singapore, Singapore, Singapore., de Silva AM; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Premkumar L; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2023 Jan 10; Vol. 19 (1), pp. e1010814. Date of Electronic Publication: 2023 Jan 10 (Print Publication: 2023).
DOI: 10.1371/journal.ppat.1010814
Abstrakt: We currently have an incomplete understanding of why only a fraction of human antibodies that bind to flaviviruses block infection of cells. Here we define the footprint of a strongly neutralizing human monoclonal antibody (mAb G9E) with Zika virus (ZIKV) by both X-ray crystallography and cryo-electron microscopy. Flavivirus envelope (E) glycoproteins are present as homodimers on the virion surface, and G9E bound to a quaternary structure epitope spanning both E protomers forming a homodimer. As G9E mainly neutralized ZIKV by blocking a step after viral attachment to cells, we tested if the neutralization mechanism of G9E was dependent on the mAb cross-linking E molecules and blocking low-pH triggered conformational changes required for viral membrane fusion. We introduced targeted mutations to the G9E paratope to create recombinant antibodies that bound to the ZIKV envelope without cross-linking E protomers. The G9E paratope mutants that bound to a restricted epitope on one protomer poorly neutralized ZIKV compared to the wild-type mAb, demonstrating that the neutralization mechanism depended on the ability of G9E to cross-link E proteins. In cell-free low pH triggered viral fusion assay, both wild-type G9E, and epitope restricted paratope mutant G9E bound to ZIKV but only the wild-type G9E blocked fusion. We propose that, beyond antibody binding strength, the ability of human antibodies to cross-link E-proteins is a critical determinant of flavivirus neutralization potency.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Adams et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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