Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage

Abstract

Objectives: Neisseria meningitidis is a leading cause of meningitis and septicaemia. The hyperinvasive ST-11 clonal complex (cc11) caused serogroup C (MenC) outbreaks in the US military in the 1960s and UK universities in the 1990s, a global Hajj-associated serogroup W (MenW) outbreak in 2000-2001, and subsequent MenW epidemics in sub-Saharan Africa. More recently, endemic MenW disease has expanded in South Africa, South America and the UK, and MenC cases have been reported among European and North American men who have sex with men (MSM). Routine typing schemes poorly resolve cc11 so we established the population structure at genomic resolution.

Methods: Representatives of these episodes and other geo-temporally diverse cc11 meningococci (n = 750) were compared across 1546 core genes and visualised on phylogenetic networks.

Results: MenW isolates were confined to a distal portion of one of two main lineages with MenB and MenC isolates interspersed elsewhere. An expanding South American/UK MenW strain was distinct from the 'Hajj outbreak' strain and a closely related endemic South African strain. Recent MenC isolates from MSM in France and the UK were closely related but distinct.

Conclusions: High resolution 'genomic' multilocus sequence typing is necessary to resolve and monitor the spread of diverse cc11 lineages globally.

Keywords: Genome; Meningococcal; ST-11 clonal complex; Serogroup C; Serogroup W.

Figure 1

Population structure and serogroup distribution among geographically and temporally diverse meningococcal cc11 isolates versus non-cc11 isolates. (a) Neighbour-net phylogenetic network based on a comparison of 1546 core genome loci among geographically and temporally diverse cc11 isolates (n = 750) and two non-cc11 isolates (cc8 and cc41/44, respectively). The cc11 isolates bifurcated into two main sublineages (lineages 11.1 and 11.2), each containing several clusters of isolates. Panel (b) illustrates the serogroup distribution whereby serogroups B (MenB) and C (MenC) were present in both sublineages while serogroup W (MenW) isolates were confined to the intermediate and distal regions of lineage 11.1. The scale bar indicates the number of differences among the 1546 loci compared.

Figure 2

Geo-temporal, serogroup and serotype distributions of meningococcal lineage 11.2 isolates and the distribution of invasive isolates from British and French men who have sex with men. The inset in section (a) indicates the region of cc11 represented by lineage 11.2. The corresponding isolates were compared, along with 71 diverse representatives of lineage 11.1 (Supplementary Table 1 – highlighted yellow), in terms of 1546 core genome loci to generate the Neighbour-net phylogenetic network in sections (a) to (d). The large arrow represents the lineage 11.1 isolates. (a) The relatively populous UK isolates (no marker) were broadly interspersed among isolates from countries representing several continents. (b) The diversification of the sublineage was reflected in the temporal distribution of the isolates, with more recent isolates often observed at the more distal regions of the lineage. Section (c) highlights the distribution of (i) serogroup B isolates which were highly interspersed among the serogroup C isolates (no markers), (ii) MenC:cc11 genomes from the Toronto MSM outbreak (Canada MSM), and (iii) the relatively diverse recent UK and French MSM cases that were interspersed with cases from the wider community. Section (d) depicts the distribution of PorA subtypes in which the isolates in the relatively proximal clusters (versus the origin of the sublineage) were mainly P1.5,2 or P1.5-1,10-4, whilst isolates within more distal clusters were mainly P1.5-1,10-8. The scale bar in section (a) indicates the number of differences among the 1546 loci compared.

Figure 3

Geo-temporal distribution of isolates within distal sublineages of meningococcal lineage 11.1. The inset (top-right) depicts a cgMLST (1546 loci) Neighbour-net phylogenetic network of all 750 geo-temporally diverse cc11 isolates and two non-cc11 isolates (cc8 and cc41/44) highlighting the distal region of lineage 11.1 that bifurcates into two sublineages. Isolates corresponding to this region underwent a separate cgMLST (1546 loci) comparison to generate the Neighbour-net network in the main figure. Both sublineages contained several clusters, each relating to a noteworthy episode of serogroup W disease. One lineage included strains relating to the Hajj outbreak of 2000 onwards (Anglo-French Hajj strain), the expansion of endemic MenW:cc11 disease in South Africa from 2003 (endemic South African Strain) and a period of MenW:cc11 epidemics in sub-Saharan Africa (Burkina Faso/North African Strains). The other sublineage contained clusters relating to expanding endemic MenW:cc11 disease in South America and the UK (the South American/UK strain). Dots relate to individual cases. The scale bar indicates the number of loci differing among the 1546 compared.