4 years ago

Heterogeneity in non-epitope loop sequence and outer membrane protein complexes alters antibody binding to the major porin protein PorB in serogroup B Neisseria meningitidis

Heterogeneity in non-epitope loop sequence and outer membrane protein complexes alters antibody binding to the major porin protein PorB in serogroup B Neisseria meningitidis
Margaret C. Bash, Wonpil Im, Hesham F. Nawar, Michael Brad Strader, Kathryn A. Matthias, Dhilon S. Patel, Joonseong Lee, Yamei S. Gao
PorB is a well-characterized outer membrane protein that is common among Neisseria species and is required for survival. A vaccine candidate, PorB induces antibody responses that are directed against six variable surface-exposed loops that differ in sequence depending on serotype. Although Neisseria meningitidis is naturally competent and porB genetic mosaicism provides evidence for strong positive selection, the sequences of PorB serotypes commonly associated with invasive disease are often conserved, calling into question the interaction of specific PorB loop sequences in immune engagement. In this report, we provide evidence that antibody binding to a PorB epitope can be altered by sequence mutations in non-epitope loops. Through the construction of hybrid PorB types and PorB molecular dynamics simulations, we demonstrate that loops both adjacent and non-adjacent to the epitope loop can enhance or diminish antibody binding, a phenotype that correlates with serum bactericidal activity. We further examine the interaction of PorB with outer membrane-associated proteins, including PorA and RmpM. Deletion of these proteins alters the composition of PorB-containing native complexes and reduces antibody binding and serum killing relative to the parental strain, suggesting that both intramolecular and intermolecular PorB interactions contribute to host adaptive immune evasion. Mosaicism is prevalent in the gene encoding the major Neisseria meningitidis outer membrane protein (OMP) PorB. In this study, we demonstrate that sequence variability in non-epitope PorB loops results in altered loop conformation and residue interaction with the bacterial membrane, leading to diminished antibody binding and complement-mediated killing. The interaction of PorB with OMPs PorA and RmpM also plays a lesser but physiologically significant role in governing the strength of antibody/PorB binding.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/mmi.13747

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