Typing of Neisseria meningitidis by whole-genome analysis
Authors: Raymond S W Tsang
Journal: The Lancet Infectious Diseases (2015)

Neisseria meningitidis is a Gram-negative diplococcal bacterium that can harmlessly inhabit the human nasopharynx. For reasons not completely understood, meningococci can invade the mucous membrane and gain access to the bloodstream, leading to meningitis, severe sepsis, or localised infections involving the joints or heart. Invasive meningococcal disease (IMD) can progress rapidly in previously healthy adolescents or young adults, is associated with mortality of about 10%, and occurs worldwide, although with geographical and topological variations in prevalence and the serogroups and clonal types of strains involved.1Leimkugel J Racioz V de Silva LJ Pluschke G Global review of meningococcal disease A shifting etiology.J Bacteriol Res. 2009; 1: 6-18Google Scholar The reasons for these variations remain unclear. Nevertheless, six serogroups (A, B, C, W, X, and Y) of 12 and a handful of clones that are defined as hypervirulent lineages cause most of the disease burden.2Caugant DA Maiden MCJ Meningococcal carriage and disease—population biology and evolution.Vaccine. 2009; 27S: B64-B70Crossref Scopus (275) Google Scholar Whole-genome sequencing (WGS) has been explored as a method for bacterial characterisation. With this technology becoming increasingly available and affordable, Dorothea Hill and colleagues,3Hill DMC Lucidarme J Gray SJ et al.Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study.Lancet Infect Dis. 2015; (published online Oct 27.)http://dx.doi.org/10.1016/S1473-3099(15)00267-4Google Scholar in The Lancet Infectious Diseases, expanded on the idea of gene-by-gene comparative analysis, originally introduced for multilocus sequencing typing (MLST),4Maiden MCJ Bygraves JA Feil E et al.Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms.Proc Natl Acad Sci USA. 1998; 95: 3140-3145Crossref PubMed Scopus (2841) Google Scholar to create a new platform called the Bacterial Isolate Genomic Sequence database that can handle WGS data.5Jolley KA Maiden MCJ BIGSdb: scalable analysis of bacterial genome variation at the population level.BMC Bioinformatics. 2010; 11: 595Crossref PubMed Scopus (1500) Google Scholar, 6Jolley KA Maiden MCJ Automated extraction of typing information for bacterial pathogens from whole genome sequence data: Neisseria meningitidis as an exemplar.Euro Surveill. 2012; 18: 20379Google Scholar, 7Maiden MCJ van Rensburg MJJ Bray JE et al.MLST revisited: the gene by gene approach to bacterial genomics.Nat Rev Microbiol. 2013; 11: 728-736Crossref PubMed Scopus (420) Google Scholar De-novo assembled draft genomes or contiguous sequences from WGS analysis can be uploaded for gene-by-gene interrogation of known alleles at multiple loci stored in the system. To investigate the usefulness of this new platform to routine surveillance, Hill and colleagues analysed WGS data for all Neisseria meningitidis IMD isolates (n=899) submitted to the Public Health England Meningococcal Reference Unit for England and Wales in the epidemiological years 2010–11 and 2011–12. Data on serogroups of cultured isolates and their de-novo draft genomes, assembled (from WGS data) by previously validated procedures, were analysed together. This platform for handling WGS data was flexible enough to allow the investigators to set the level and the type of analysis they required on the basis of clinical or research questions. For example, typing could be done with the conventional seven genes used in MLST, 49 ribosomal protein gene loci, or 1605 core-genome MLST. The inclusion of genes associated with antibiotic susceptibility or vaccine antigen targets into the analysis can be used to predict antibiotic susceptibility and vaccine coverage. Hill and colleagues identified at least 20 meningococcal lineages showing substantial strain diversity and extensive recombination. Hyperinvasive clonal complexes 41/44 (lineage 3), 269 (lineage 2), and 23 (lineage 23) accounted for 528 (59%) of IMD isolates. Coupling of the WGS analysis with patients' demographic data enabled investigation of the relation between meningococcal lineages and disease in different age groups. Hill and colleagues found that specific lineages were strongly associated with IMD in particular age groups and that diversity was substantial in the youngest and oldest individuals. The allelic analysis of WGS data also showed high diversity of the meningococcal group B vaccine antigens among clinical isolates, which might help to predict strain coverage of the Bexsero group B vaccine (GlaxoSmithKline, Brentford, Middlesex, UK), which is now available in the UK. The high resolution of ribosomal and core-genome MLST defined several sublineages, for instance in lineage 11 (clonal complex 11) and lineage 2 (clonal complex 269). Sublineage 11.1 corresponds to the classic ET-37 clonal complex8Wang JF Caugant DA Morelli G Koumare B Achtman M Antigenic and epidemiological properties of the ET-37 complex of Neisseria meningitidis.J Infect Dis. 1993; 167: 1320-1329Crossref PubMed Scopus (127) Google Scholar and sublineage 11.2 corresponds to the ET-15 variant of the parent ET-37 clonal complex.9Jelfs J Munro R Ashton FE Caugant DA Genetic characterization of a new variant within the ET-37 complex of Neisseria menigitidis associated with outbreaks in various parts of the world.Epidemiol Infect. 2000; 125: 285-298Crossref PubMed Scopus (43) Google Scholar Although use of meningococcal serogroup C conjugate vaccine has reduced the disease burden to a minimum, low levels of activity remain in the UK. In Canada, reduction in meningococcal serogroup C levels has been associated with a concomitant shift in strain from the predominant ET-15 (lineage 11.2) to ET-37 (lineage 11.1), as confirmed with antigenic and genetic analyses.10Tsang RSW Hoang L Tyrrell G et al.Genetic and antigenic characterization of Canadian invasive Neisseria meningitidis serogroup C (MenC) case isolates in the post-MenC conjugate vaccine era, 2009-2013.J Med Microbiol. 2015; 64: 174-179Crossref PubMed Scopus (2) Google Scholar With use of WGS data, lineage 2 has been resolved into sublineages 2.1 and 2.2, for which the corresponding founding sequence types are 269 and 275, respectively. In the UK, prevalence of these two sublineages has fluctuated over time,11Lucidarme J Comanducci M Findlow J et al.Characterization of fHbp, nhba (gna2132), nadA, porA, sequence type (ST), and genomic presence of IS1301 in group B meningococcal ST-269 clonal complex isolates from England and Wales.J Clin Microbiol. 2009; 47: 3577-3585Crossref PubMed Scopus (66) Google Scholar whereas in Canada strains of lineage 2.1 have been persistently common and have caused localised outbreaks since first emerging in Quebec in 2003.12Zhou J Lefebvre B Deng S et al.Invasive serogroup B Neisseria meningitidis in Quebec, Canada, 2003 to 2010: persistence of the ST-269 clone since it first emerged in 2003.J Clin Microbiol. 2012; 50: 1545-1551Crossref PubMed Scopus (29) Google Scholar, 13Law DKS Lefebvre B Gilca R et al.Characterization of invasive Neisseria meningitidis strains from Quebec, Canada, during a period of increased serogroup B disease, 2009–2013: phenotyping and genotyping with special emphasis on the non-carbohydrate protein vaccine targets.BMC Microbiol. 2015; 15: 143Crossref PubMed Scopus (18) Google Scholar The WGS typing platform described by Hill and colleagues3Hill DMC Lucidarme J Gray SJ et al.Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study.Lancet Infect Dis. 2015; (published online Oct 27.)http://dx.doi.org/10.1016/S1473-3099(15)00267-4Google Scholar is a suitable method for studying the epidemiology of IMD in England and Wales. The robustness and user-friendly and portable features might prove to be useful for worldwide analysis of IMD, including comparison of strain characteristics of similar or identical lineages in different regions where epidemiology differs. I declare no competing interests. The opinion expressed in this comment is my personal opinion and does not represent the view of the Public Health Agency of Canada. Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort studyThe MRF-MGL represents an effective, broadly applicable model for the storage, analysis, and dissemination of WGS data that can facilitate real-time genomic pathogen surveillance. The data revealed information crucial to effective deployment and assessment of vaccines against N meningitidis. Full-Text PDF Open Access