title: Transcriptomic buffering of cryptic genetic variation contributes to meningococcal virulence.
abstract: Commensal 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.
  
  
  
  Despite 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.
  
  
  
  Our 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.
authors.affiliation: Institute for Hygiene and Microbiology, Joseph-Schneider-Straße 2, University of Würzburg, 97080, Würzburg, Germany.
authors.forename: Biju Joseph
authors.initials: BJ
authors.lastname: Ampattu
authors.affiliation: Institute for Hygiene and Microbiology, Joseph-Schneider-Straße 2, University of Würzburg, 97080, Würzburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Hagmann
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.|Department of Human Genetics, Biocenter, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dittrich
authors.affiliation: Center for Biotechnology (CeBiTec), Bielefeld University, Universitätsstr. 27, 33615, Bielefeld, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlüter
authors.affiliation: Institute for Bioinformatics and Systems Biology, Justus Liebig University Gießen, Heinrich-Buff-Ring 58, 35392, Gießen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Blom
authors.affiliation: LOEWE-Center for Synthetic Microbiology, Hans-Meerwein-Straße, 35032, Marburg, Germany.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Krol
authors.affiliation: Institute for Bioinformatics and Systems Biology, Justus Liebig University Gießen, Heinrich-Buff-Ring 58, 35392, Gießen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Goesmann
authors.affiliation: LOEWE-Center for Synthetic Microbiology, Hans-Meerwein-Straße, 35032, Marburg, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Becker
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dandekar
authors.affiliation: Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.affiliation: Institute for Hygiene and Microbiology, Joseph-Schneider-Straße 2, University of Würzburg, 97080, Würzburg, Germany. cschoen@hygiene.uni-wuerzburg.de.
authors.forename: Christoph
authors.identifier: 0000-0003-2222-1085
authors.initials: C
authors.lastname: Schoen
mesh_terms: D015373:Bacterial Typing Techniques; D015415:Biomarkers; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D005809:Genes, Regulator; D014644:Genetic Variation; D016680:Genome, Bacterial; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008585:Meningitis, Meningococcal / Q000097:blood / Q000378:metabolism / Q000382:microbiology; D058977:Molecular Sequence Annotation; D009345:Neisseria meningitidis / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity; D010641:Phenotype; D011401:Promoter Regions, Genetic; D059467:Transcriptome; D014774:Virulence / Q000235:genetics*
chemical_list: D015415:Biomarkers
keywords: Cryptic genetic variation; MITE; Metabolism; Neisseria meningitidis; Regulatory evolution; RelA; Stringent response; Systems biology; Virulence