Abstract
Neisseria meningitidis is a Gram-negative bacterial pathogen that causes life threatening meningitis and septicemia. Neisseria Heparin Binding Antigen (NHBA) is an outer membrane protein that binds heparin and heparan sulfate and DNA. This protein is one of the four antigens in the meningococcal serogroup B vaccine Bexsero. In the current study, we sought to define the full glycan-binding repertoire of NHBA to better understand its role in meningococcal pathogenesis and vaccine efficacy. Glycan array analysis revealed binding to 28 structures by recombinant NHBA. Surface plasmon resonance was used to confirm the binding phenotype and to determine the affinity of the interactions. These studies revealed that the highest affinity binding of NHBA was with chondroitin sulfate (KD = 5.2 nM). This affinity is 10-fold higher than observed for heparin. Analysis of binding with well-defined disaccharides of the different chondroitin sulfate types demonstrated that the most preferred ligand has a sulfate at the 2 position of the GlcA/IdoA and 6 position of the GalNAc, which is an equivalent structure to chondroitin sulfate D. Chondroitin sulfate is widely expressed in human tissues, while chondroitin sulfate D is predominantly expressed in the brain and may constitute a new receptor structure for meningococci.
Highlights
Neisseria meningitidis is a Gram-negative bacterial pathogen that causes life threatening meningitis and septicemia[1]
Twenty-two of these structures were in common with those bound by the Neisseria Heparin Binding Antigen (NHBA) expressing strain
Some of the recombinant NHBA-binding glycan structures were not bound by the wild type, possibly due to interactions being blocked on the bacterial surface by the presence of other meningococcal components, such as lipooligosaccharide (LOS)[17,18] or pili[18,19] that can negatively affect interactions mediated by other structures
Summary
Neisseria meningitidis is a Gram-negative bacterial pathogen that causes life threatening meningitis and septicemia[1]. In 2013, a serogroup B vaccine (4CMenB, Bexsero) was licensed for use This vaccine contains four components; outer membrane vesicles from a serogroup B strain, formulated with three recombinant proteins NadA, fHBP and NHBA6,7. These outer membrane proteins provide targets for complement-mediated serum bactericidal activity[6]. They provide an opportunity for functional blocking as each is proposed to play a key role in N. meningitidis pathogenesis, and understanding the functional roles of these surface antigens enables a better understanding of how the vaccine is functioning to protect against infection. We sought to investigate the full range of lectin activity of NHBA using glycan array analysis
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