Metabolic shift in the emergence of hyperinvasive pandemic meningococcal lineages

Abstract

Hyperinvasive lineages of Neisseria meningitidis, which persist despite extensive horizontal genetic exchange, are a major cause of meningitis and septicaemia worldwide. Over the past 50 years one such lineage of meningococci, known as serogroup A, clonal complex 5 (A:cc5), has caused three successive pandemics, including epidemics in sub-Saharan Africa. Although the principal antigens that invoke effective immunity have remained unchanged, distinct A:cc5 epidemic clones have nevertheless emerged. An analysis of whole genome sequence diversity among 153 A:cc5 isolates identified eleven genetic introgression events in the emergence of the epidemic clones, which primarily involved variants of core genes encoding metabolic processes. The acquired DNA was identical to that found over many years in other, unrelated, hyperinvasive meningococci, suggesting that the epidemic clones emerged by acquisition of pre-existing metabolic gene variants, rather than 'virulence' associated or antigen-encoding genes. This is consistent with mathematical models which predict the association of transmission fitness with the emergence and maintenance of virulence in recombining commensal organisms.

Figure 1. Geographic, genetic and antigenic diversity of 153 serogroup A isolates belonging to the ST-5 complex.

(A) Global spread of the ST-5 complex in three successive pandemics (red: first pandemic wave; blue: second pandemic wave; green: third pandemic wave; yellow: ST-2859). (B) Allele-based phylogenetic network of 153 whole genomes of the ST-5 complex. (C) Pie-charts of allelic diversity of six major sub-capsular antigens across the 153 isolates. Most isolates had a highly consistent antigenic profile, with a single dominant allele found for each antigen (PorA: 97.4% = allele P1.20,9; FetA: 97.4% = allele F3-1; PorB: 92.1% = allele 3–47; NadA: 99.3% = allele 7; OpcA: 96.1% = allele 3; fHbp: 83.1% = allele 39). PorA, FetA, PorB, NadA and fHbp have all been shown to induce an immune response and deployed in various protein-based vaccines. See also Table S7. The maps were created using mapchart.net (www.mapchart.net).

Figure 2. Functional characterisation and location of alleles specific to each epidemic wave.

(A) Functional characterisations of alleles specific to each epidemic wave. (B) Plots of successive allelic changes against their position in the reference genome for each epidemic wave, with an accompanying plot of these changes annotated on the circular chromosome of Z2491 (or WUE2594 for ST-2859). Letters indicate areas of allelic changes which are adjacent on the chromosome. (C) Genomic areas of putative recombination between ST-2859 and ST-11/ST-167 strains. Comparison plots show hypothetical donor strains on the bottom level (either reference strain FAM18, an isolate of serogroup C ST-11, or M12 240332, a serogroup Y ST-167 complex strain), ST-2859 on the central level (isolate ERR052831), and reference strain WUE 2594 (serogroup A, ST-5 complex) on the top level (representative of the recipient strain). The arrows signify putative areas of recombination, and correspond to higher sequence identity shared between FAM18/M12 240332 and ST-2859, than the ancestral WUE 2594 strain and ST2859.