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

Area of Science:

• Microbiology
• Vaccinology
• Genetics

Background:

• Serogroup B Neisseria meningitidis causes significant global health issues, with no current comprehensive vaccines.
• Challenges in developing conjugate vaccines for serogroup B meningococcus stem from poor immunogenicity and molecular mimicry of human sialic acids.
• Outer-membrane protein (OMP)-based vaccines are being explored, but meningococcal genetic and antigenic diversity complicates their design.

Purpose of the Study:

• To investigate the genetic diversity of the Neisseria meningitidis outer-membrane protein HmbR.
• To understand how HmbR diversity is structured among major hyper-invasive meningococcal lineages.
• To inform the selection of OMP-based vaccine candidates by characterizing HmbR variability.

Main Methods:

• Analysis of hmbR gene sequences from N. meningitidis isolates representing key hyper-invasive lineages.
• Application of genealogical analysis to understand the evolutionary history of hmbR genes.
• Identification and characterization of variable regions within the HmbR protein using 2D modeling.

Main Results:

• The genetic diversity of hmbR arises from horizontal genetic exchange and de novo mutation.
• Genealogical analysis revealed an association between hmbR genes and specific clonal complexes, with two distinct hmbR families (A and B) identified.
• Three variable regions (VR1-VR3) were found in surface-exposed loops, exhibiting structuring related to clonal complexes, with some codons under diversifying selection.

Conclusions:

• The diversity of HmbR is structured and influenced by evolutionary processes like recombination and mutation.
• Understanding HmbR diversity is crucial for designing effective outer-membrane protein-based vaccines against serogroup B Neisseria meningitidis.
• Specific variable regions under diversifying selection may represent key targets for immune responses.