Transcriptomic buffering of cryptic genetic variation contributes to meningococcal virulence

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3616-7) contains supplementary material, which is available to authorized users.

Anticoagulants impact on innate immune responses and bacterial survival in whole blood models of Neisseria meningitidis infection

“…Thus, although our study only takes into account a small number of strains, it appears that survival and growth of N . meningitidis strains is not solely determined by their serogroup or overall genetic similarity as per sequence type, which is in line with the notion that meningococcal virulence is a polygenic trait and that the characterization of distinct genetic elements responsible for their invasiveness are obscured by the high genetic diversity of this species 14 , 33 , 51 .…”

“…An overview of the characteristics of the chosen strains is shown in Supplementary Table S1 . We matched two pairs of carriage versus invasive strains which share high genomic homology in this study: MC58 (ST-74, cc32, IMD) versus α522 (ST-35, cc35, carriage) 14 , 33 as well as 8013 (ST-177, cc18, IMD) versus α4 (ST-19, cc18, carriage) 34 .…”

“…Indeed, whole blood models of IMD have been widely used in studies monitoring transcriptome dynamics of N . meningitidis 14 – 16 , the influence of meningococcal virulence factors 17 – 19 , the effect of complement factors 20 , 21 and the impact of cellular effectors on IMD 22 .…”

“…The most commonly used anticoagulants in studies regarding N . meningitidis whole blood infections are citrate 17 , 18 , heparin 14 – 16 , 23 and hirudin (or its derivate lepirudin) 20 , 21 , 24 , 25 . These three anticoagulants inhibit coagulation by different mechansims: Citrate sequesters free Ca 2+ , a crucial co-factor of coagulation; the polyanionic glucosaminoglycan heparin inhibits coagulation mainly by enhancing the activity of antithrombin III; hirudin and its derivates directly bind to and irreversibly inhibit thrombin 26 .…”

Neisseria genomics: current status and future perspectives

“…Consequently, while both meningococci were able to grow in human blood, they showed significant differences in the expression of numerous virulence-associated determinants suggesting that meningococcal virulence was linked to transcriptional buffering of cryptic genetic variation in metabolic genes (Ampattu et al. 2017 ).…”