Abstract
BackgroundCommensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain α522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence.ResultsDespite indistinguishable ex vivo phenotypes, both strains differed in the expression of over 500 genes under infection mimicking conditions. These differences comprised in particular metabolic and information processing genes as well as genes known to be involved in host-damage such as the nitrite reductase and numerous LOS biosynthesis genes. A model based analysis of the transcriptomic differences in human blood suggested ensuing metabolic flux differences in energy, glutamine and cysteine metabolic pathways along with differences in the activation of the stringent response in both strains. In support of the computational findings, experimental analyses revealed differences in cysteine and glutamine auxotrophy in both strains as well as a strain and condition dependent essentiality of the (p)ppGpp synthetase gene relA and of a short non-coding AT-rich repeat element in its promoter region.ConclusionsOur data suggest that meningococcal virulence is linked to transcriptional buffering of cryptic genetic variation in metabolic genes including global stress responses. They further highlight the role of regulatory elements for bacterial virulence and the limitations of model strain approaches when studying such genetically diverse species as N. meningitidis.
Highlights
Commensal bacteria like Neisseria meningitidis sometimes cause serious disease
The analysis of meningococcal population genetic structure by multilocus sequence typing (MLST) demonstrated that disease-causing meningococci do belong to particular groups of related sequence types (STs), termed clonal complexes (CCs), which are overrepresented in disease isolates relative to their carriage prevalences and are responsible for most disease [2]
The 10% most divergent orthologous genes (BSRP < 0.933, n = 177) were significantly enriched for genes involved in cell motility (COG N, odds ratio (OR) = 3.8, false discovery rate (FDR) = 0.031, Fisher’s exact test with Benjamini-Hochberg multiple testing correction) as well as secretion and transport (COG U, Odds ratio (OR) = 2.6, FDR < 0.05)
Summary
Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. The analysis of meningococcal population genetic structure by multilocus sequence typing (MLST) demonstrated that disease-causing meningococci do belong to particular groups of related sequence types (STs), termed clonal complexes (CCs), which are overrepresented in disease isolates relative to their carriage prevalences and are responsible for most disease [2]. These data indicate that the propensity to cause invasive disease is somehow associated with the genetic make-up of hyperinvasive lineages. Experimental observations along with epidemiological models further indicate that genetic differences in metabolic genes might have a central role in the observed virulence differences among different lineages in a yet to define manner [9, 10]
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