Meningococcal Genetic Variation Mechanisms Viewed through Comparative Analysis of Serogroup C Strain FAM18

Abstract

The bacterium Neisseria meningitidis is commonly found harmlessly colonising the mucosal surfaces of the human nasopharynx. Occasionally strains can invade host tissues causing septicaemia and meningitis, making the bacterium a major cause of morbidity and mortality in both the developed and developing world. The species is known to be diverse in many ways, as a product of its natural transformability and of a range of recombination and mutation-based systems. Previous work on pathogenic Neisseria has identified several mechanisms for the generation of diversity of surface structures, including phase variation based on slippage-like mechanisms and sequence conversion of expressed genes using information from silent loci. Comparison of the genome sequences of two N. meningitidis strains, serogroup B MC58 and serogroup A Z2491, suggested further mechanisms of variation, including C-terminal exchange in specific genes and enhanced localised recombination and variation related to repeat arrays. We have sequenced the genome of N. meningitidis strain FAM18, a representative of the ST-11/ET-37 complex, providing the first genome sequence for the disease-causing serogroup C meningococci; it has 1,976 predicted genes, of which 60 do not have orthologues in the previously sequenced serogroup A or B strains. Through genome comparison with Z2491 and MC58 we have further characterised specific mechanisms of genetic variation in N. meningitidis, describing specialised loci for generation of cell surface protein variants and measuring the association between noncoding repeat arrays and sequence variation in flanking genes. Here we provide a detailed view of novel genetic diversification mechanisms in N. meningitidis. Our analysis provides evidence for the hypothesis that the noncoding repeat arrays in neisserial genomes (neisserial intergenic mosaic elements) provide a crucial mechanism for the generation of surface antigen variants. Such variation will have an impact on the interaction with the host tissues, and understanding these mechanisms is important to aid our understanding of the intimate and complex relationship between the human nasopharynx and the meningococcus.

Sequence analysis of the PIP5K locus in Eimeria maxima provides further evidence for eimerian genome plasticity and segmental organization

“…This further supports the notion that Rsegments serve as recombination hot spots promoting chromosomal rearrangements. Some pathogenic prokaryotes are also known for their potential in utilizing TEs for facilitating genome rearrangements that can influence the gene regulation activities of disease-associated genes (Hacker et al, 2003;Bentley et al, 2007). The accumulated evidence from previously reported findings, especially in genomes of pathogens (Hjerde et al, 2008), Drosophila (Lim and Simmons, 1994), yeast (Kim et al, 1998), nematodes (Stein et al, 2003), and humans (Sen et al, 2006), indirectly support the notion that TEs and repetitive DNAs locating in the R-segments may play a role in facilitating rearrangement in eimerian genomes.…”

Genetic and Structural Characterization of L11 Lipooligosaccharide from Neisseria meningitidis Serogroup A Strains

“…Homopolymeric tracts were determined by comparison with reference sequences (18,19,24,25,33,34). DNA sequences were analyzed with Vector NTi (Invitrogen).…”

Bexsero

“…The inclusion of multiple antigens reduces the risk of escape variants, which could easily occur with a vaccine reliant on a single antigen given the high rate of phase variation, recombination and mutation in N. meningitidis. 40 Neisserial strains could also escape immune responses against the vaccine antigens by changing the expression levels of the target antigens through different mechanisms. For example, only 50% of invasive meningococcal isolates are known to produce NadA in detectable quantities (nadA expression is phase variable) with a significant proportion of the NadA negative isolates not having the nadA gene at all.…”