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

Abstract

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 analysed 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. Conclusion 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 colonisation, thereby increasing the risk of disease in vulnerable older people with altered nasopharyngeal microbiomes and nutritional status.

Genetic variants linked to the phenotypic outcome of invasive disease and carriage of Neisseria meningitidis

“…Few GWAS studies have been performed on N. meningitidis , and few similarities were found to this study [ 23, 67, 75 ]. These studies have found carriage-derived k-mers in the tspB gene [ 67 ], associations of tbpB with invasive serogroup Y, cc23 isolates [ 75 ] , and another study found the gene NEIS0975 associated with invasive isolates [ 23 ], which we here found to be associated with carriage. These studies focused on one serogroup or CC, which may explain why we found different variants as we studied the entire N. meningitidis population from 2018 to 2019 in Sweden.…”

“…Despite adjustment for population structure as part of the GWAS approach, some results in this study may have been affected by the lower frequency of genetic variants among the major serogroups of the invasive isolates in Sweden. Few GWAS studies have been performed on N. meningitidis, and few similarities were found to this study [23,67,75]. These studies have found carriage-derived k-mers in the tspB gene [67], associations of tbpB with invasive serogroup Y, cc23 isolates [75], and another study found the gene NEIS0975 associated with invasive isolates [23], which we here found to be associated with carriage.…”