Genome-wide association studies reveal the role of polymorphisms affecting factor H binding protein expression in host invasion by Neisseria meningitidis

Abstract

Many invasive bacterial diseases are caused by organisms that are ordinarily harmless components of the human microbiome. Effective interventions against these microbes require an understanding of the processes whereby symbiotic or commensal relationships transition into pathology. Here, we describe bacterial genome-wide association studies (GWAS) of Neisseria meningitidis, a common commensal of the human respiratory tract that is nevertheless a leading cause of meningitis and sepsis. An initial GWAS discovered bacterial genetic variants, including single nucleotide polymorphisms (SNPs), associated with invasive meningococcal disease (IMD) versus carriage in several loci across the meningococcal genome, encoding antigens and other extracellular components, confirming the polygenic nature of the invasive phenotype. In particular, there was a significant peak of association around the fHbp locus, encoding factor H binding protein (fHbp), which promotes bacterial immune evasion of human complement by recruiting complement factor H (CFH) to the meningococcal surface. The association around fHbp with IMD was confirmed by a validation GWAS, and we found that the SNPs identified in the validation affected the 5’ region of fHbp mRNA, altering secondary RNA structures, thereby increasing fHbp expression and enhancing bacterial escape from complement-mediated killing. This finding is consistent with the known link between complement deficiencies and CFH variation with human susceptibility to IMD. These observations demonstrate the importance of human and bacterial genetic variation across the fHbp:CFH interface in determining IMD susceptibility, the transition from carriage to disease.

The bacterial genetic determinants ofEscherichia colicapacity to cause bloodstream infections in humans

“…The present study compares E. coli whole genomes in colonization and in infection, as done before for Klebsellia pneumoniae (52), S. pneumoniae (55), Staphylococcus aureus (53, 56), Neisseria meningitidi s (57). These GWAS studies presented a range of results, from low heritability (2.6% for S. aureus carriage vs. BSI (53)), to intermediate (36.5% for N. meningitidis carriage vs. invasive meningococcal disease), and an analogously large heritability of 70% for S. pneumoniae invasive disease vs. carriage, along with a handful of significant SNPs (55).…”

Acquisition, co-option, and duplication of thertxtoxin system and the emergence of virulence inKingella

“…The preexisting TISS is most closely related to genes of the frp operon, which encodes the distantly related RTX family protein, FrpC, and is intact in N. meningitidis but not in N. gonorrhoeae or commensal Neisseria speices 54,55 . Though the specific function of FrpC is unclear, it is thought to act as an additional adhesin that is dispensable for virulence in a mouse model [56][57][58][59][60] . This important genetic reconstitution event provides a novel example of gene co-option as a major contributing factor in the evolution of bacterial virulence in a commensal genus.…”

Improved interpretability of bacterial genome-wide associations using gene cluster centric k-mers

“…panfeed was also tested for its ability to interpret bacterial GWAS results on a dataset of 1556 N. meningitidis strains 6 . Unlike the original study, we ran an analysis pooling the discovery and the replication data sets.…”

“…The second dataset we used to test panfeed consists of 1,556 N. meningitidis strains, for which phenotypic data on the induction of invasive meningococcal disease (IMD) in their hosts was measured 6 . Earle et al found a SNP in the 5' untranslated region of fHbp (fHbp-7T) that was significantly associated with IMD-positive strains in a discovery and replication dataset consisting of a total of 1,556 strains.…”

“…These include virulence and pathogenicity 1 , antimicrobial resistance 2,3 , host range 4 and carriage duration 5 . In many cases, statistically associated variants were verified to be causal for the phenotype through forward genetic techniques 1,6 , proving the power of the approach and its usefulness to elucidate crucial aspects of bacterial infections 7,8 .…”