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Transcriptomic buffering of cryptic genetic variation contributes to meningococcal virulence
Biju Joseph Ampattu1, Laura Hagmann1, Chunguang Liang2
1Institute for Hygiene and Microbiology, Joseph-Schneider-Straße 2, University of Würzburg, 97080, Würzburg, Germany.
Background:
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.
Results:
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.
Conclusions:
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.
Insights
Neisseria meningitidis virulence is linked to gene regulation, not just genetic differences. Transcriptional control of metabolic genes and stress responses influences bacterial disease potential.
Area of Science:
- Microbiology
- Genomics
- Systems Biology
Background:
- Neisseria meningitidis can transition from commensal to pathogenic.
- Genomic comparisons have not clearly identified key virulence factors.
- Understanding gene regulation is crucial for meningococcal virulence.
Purpose of the Study:
- Compare gene expression between invasive and carriage strains of N. meningitidis.
- Investigate the role of gene regulation in meningococcal virulence.
- Assess strain-specific gene expression under conditions mimicking host environments.
Main Methods:
- Systems biology approach comparing gene expression.
- Ex vivo culture conditions mimicking commensal and virulence environments.
- Transcriptomic analysis and computational modeling.
Main Results:
- Over 500 genes differed in expression between strains under infection-mimicking conditions.
- Differences observed in metabolic, information processing, and host-damage related genes (e.g., nitrite reductase, LOS biosynthesis).
- Computational models predicted metabolic flux differences and stringent response activation; experimental data confirmed auxotrophies and essentiality of relA gene.
Conclusions:
- Meningococcal virulence is associated with transcriptional buffering of metabolic gene variations and stress responses.
- Regulatory elements play a significant role in bacterial virulence.
- Model strain approaches have limitations for studying genetically diverse bacteria like N. meningitidis.