Structure of a protective epitope reveals the importance of acetylation of Neisseria meningitidis serogroup A capsular polysaccharide

Autor: Lucia Dello Iacono, Jesús Jiménez-Barbero, Rino Rappuoli, Francesco Berti, Alessia Biolchi, Maria Rosaria Romano, Gonҫalo J. L. Bernardes, Roberto Adamo, Pedro Henriques, Ana Ardá, Ana Gimeno
Přispěvatelé: European Commission, Repositório da Universidade de Lisboa, Gimeno, Ana [0000-0001-9668-2605], Biolchi, Alessia [0000-0001-5104-5522], Jimenez-Barbero, Jesus [0000-0001-5421-8513], Rappuoli, Rino [0000-0002-8827-254X], Adamo, Roberto [0000-0001-5228-6088], Apollo - University of Cambridge Repository
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
conformation
Glycoconjugate
design
carbohydrates
shigella-flexneri
Serum Bactericidal Antibody Assay
Neisseria meningitidis
Crystallography
X-Ray
medicine.disease_cause
01 natural sciences
Epitope
Epitopes
Immunology and Inflammation
Immunogenicity
Vaccine
NMR-spectroscopy
Multicenter Studies as Topic
Child
Randomized Controlled Trials as Topic
chemistry.chemical_classification
0303 health sciences
Multidisciplinary
biology
Polysaccharides
Bacterial
Acetylation
Biological Sciences
vaccines
Antibodies
Bacterial
3. Good health
Molecular Docking Simulation
Female
African meningitis belt
Antibody
O-acetylation
Adolescent
medicine.drug_class
Meningococcal Vaccines
macromolecular substances
Meningitis
Meningococcal
Serogroup
010402 general chemistry
Monoclonal antibody
antibody recognition
Microbiology
Immunoglobulin Fab Fragments
03 medical and health sciences
Clinical Trials
Phase II as Topic
antigen
Antigen
evolution
medicine
Humans
030304 developmental biology
Vaccines
Conjugate
0104 chemical sciences
structural glycobiology
chemistry
Polyclonal antibodies
biology.protein
monoclonal-antibody
Zdroj: 'Proceedings of the National Academy of Sciences of the USA ', vol: 117, pages: 29795-29802 (2020)
Addi. Archivo Digital para la Docencia y la Investigación
instname
Proceedings of the National Academy of Sciences of the United States of America
Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
Addi: Archivo Digital para la Docencia y la Investigación
Universidad del País Vasco
ISSN: 0027-8424
Popis: Copyright © 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Meningococcal meningitis remains a substantial cause of mortality and morbidity worldwide. Until recently, countries in the African meningitis belt were susceptible to devastating outbreaks, largely attributed to serogroup A Neisseria meningitidis (MenA). Vaccination with glycoconjugates of MenA capsular polysaccharide led to an almost complete elimination of MenA clinical cases. To understand the molecular basis of vaccine-induced protection, we generated a panel of oligosaccharide fragments of different lengths and tested them with polyclonal and monoclonal antibodies by inhibition enzyme-linked immunosorbent assay, surface plasmon resonance, and competitive human serum bactericidal assay, which is a surrogate for protection. The epitope was shown to optimize between three and six repeating units and to be O-acetylated. The molecular interactions between a protective monoclonal antibody and a MenA capsular polysaccharide fragment were further elucidated at the atomic level by saturation transfer difference NMR spectroscopy and X-ray crystallography. The epitope consists of a trisaccharide anchored to the antibody via the O- and N-acetyl moieties through either H-bonding or CH–π interactions. In silico docking showed that 3-O-acetylation of the upstream residue is essential for antibody binding, while O-acetate could be equally accommodated at three and four positions of the other two residues. These results shed light on the mechanism of action of current MenA vaccines and provide a foundation for the rational design of improved therapies.
This work was sponsored by GlaxoSmithKline Biologicals and has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie Grant Agreement 675671.
Databáze: OpenAIRE
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