Evolution of Sequence Type 4821 Clonal Complex Meningococcal Strains in China from Prequinolone to Quinolone Era, 1972-2013

Abstract

The expansion of hypervirulent sequence type 4821 clonal complex (CC4821) lineage Neisseria meningitidis bacteria has led to a shift in meningococcal disease epidemiology in China, from serogroup A (MenA) to MenC. Knowledge of the evolution and genetic origin of the emergent MenC strains is limited. In this study, we subjected 76 CC4821 isolates collected across China during 1972-1977 and 2005-2013 to phylogenetic analysis, traditional genotyping, or both. We show that successive recombination events within genes encoding surface antigens and acquisition of quinolone resistance mutations possibly played a role in the emergence of CC4821 as an epidemic clone in China. MenC and MenB CC4821 strains have spread across China and have been detected in several countries in different continents. Capsular switches involving serogroups B and C occurred among epidemic strains, raising concerns regarding possible increases in MenB disease, given that vaccines in use in China do not protect against MenB.

Keywords: CC4821; China; Neisseria meningitidis; ST-4821 complex; bacteria; bacterial infections; clonal complex; genetic recombination; meningitis/encephalitis; meningococci; quinolone; serogroup.

Figure 1

Core genome phylogenetic tree showing relationships between Neisseria meningitidis serogroups C and B CC4821 strains, China, 1972–2011. The strains cluster within 1 of 2 distinct phylogenetic groups, group 1 and group 2. Within group 1 is an antigenically distinct clonal group (epidemic clone) containing outbreak-associated strains. Tree is rooted using serogroup A reference strain (Z2491) as an outgroup. Maximum-likelihood phylogenetic trees of aligned core genome sequences were generated under a general time reversible model of evolution with gamma rate heterogeneity, with 1,000 rapid bootstrap replicates represented as a percentage. Only node labels with >80% bootstrap support are shown. Strain type and date and place of isolation are shown; + indicates strains isolated from invasive disease cases. Resistant point mutations on the T91 position of gyrA gene are shown alongside data on gyrA allele designation. Scale bar represents total substitutions per site. CC, clonal complex; PorA VR, outer membrane protein PorA variable regions; Sg, serogroup; ST, sequence type.

Figure 2

Genetic diversity within capsule and major antigen encoding genes among 32 Neisseria meningitidis clonal complex 4821 isolates, China, 1972–2011. Gene sequences from 32 clonal complex 4821 isolates were compared with the epidemic reference strain 053442 (the topmost isolate on the juxtaposed core genome phylogenetic tree). Scale bar represents total substitutions per site. SNP, single-nucleotide polymorphism.