Genome-Wide Association Studies Identify an Association of Transferrin Binding Protein B Variation and Invasive Serogroup Y Meningococcal Disease in Older Adults

BACKGROUND: Neisseria meningitidis serogroup Y, especially ST-23 clonal complex (Y:cc23), represents a larger proportion of invasive meningococcal disease (IMD) in older adults compared to younger individuals. This study explored the meningococcal genetic variation underlying this association. METHODS: Maximum-likelihood phylogenies and the pangenome were analyzed using whole-genome sequence (WGS) data from 200 Y:cc23 isolates in the Neisseria PubMLST database. Genome-wide association studies (GWAS) were performed on WGS data from 250 Y:cc23 isolates from individuals with IMD aged ≥65 years versus < 65 years. RESULTS: Y:cc23 meningococcal variants did not cluster by age group or disease phenotype in phylogenetic analyses. Pangenome comparisons found no differences in presence or absence of genes in IMD isolates from the different age groups. GWAS identified differences in nucleotide polymorphisms within the transferrin-binding protein B (tbpB) gene in isolates from individuals ≥65 years of age. TbpB structure modelling suggests these may impact binding of human transferrin. CONCLUSIONS: These data suggest differential iron scavenging capacity amongst Y:cc23 meningococci isolated from older compared to younger patients. Iron acquisition is essential for many bacterial pathogens including the meningococcus. These polymorphisms may facilitate colonization, thereby increasing the risk of disease in vulnerable older people with altered nasopharyngeal microbiomes and nutritional status.