Variation and molecular evolution of HmbR, the Neisseria meningitidis haemoglobin receptor

Abstract

Meningococcal disease caused by serogroup BNeisseria meningitidisremains an important health problem in many parts of the world, and there are currently no comprehensive vaccines. Poor immunogenicity, combined with immunological identity to human sialic acids, have hindered the development of a serogroup B conjugate vaccine, resulting in the development of alternative vaccine candidates, including many outer-membrane protein (OMP)-based formulations. However, the design of protein-based meningococcal vaccines is complicated by the high level of genetic and antigenic diversity of the meningococcus. Knowledge of the extent and structuring of this diversity can have implications for the use of particular proteins as potential vaccine candidates. With this in mind, the diversity of the meningococcal OMP HmbR was investigated amongN. meningitidisisolates representative of major hyper-invasive lineages. In common with other meningococcal antigens, the genetic diversity ofhmbRresulted from a combination of intraspecies horizontal genetic exchange andde novomutation. Furthermore, genealogical analysis showed an association ofhmbRgenes with clonal complexes and the occurrence of twohmbRfamilies, A and B. Three variable regions (VR1–VR3), located in loops 2, 3 and 4, were observed with clonal complex structuring of VR types. A minority of codons (3.9 %), located within putative surface-exposed loop regions of a 2D model, were under diversifying selection, indicating regions of the protein likely to be subject to immune attack.