Regulation of CovR expression in Group B Streptococcus impacts blood–brain barrier penetration
Open Access
- 5 July 2010
- journal article
- Published by Wiley in Molecular Microbiology
- Vol. 77 (2), 431-443
- https://doi.org/10.1111/j.1365-2958.2010.07215.x
Abstract
Group B Streptococcus (GBS) is an important cause of invasive infections in humans. The pathogen encodes a number of virulence factors including the pluripotent β‐haemolysin/cytolysin (β‐H/C). As GBS has the disposition of both a commensal organism and an invasive pathogen, it is important for the organism to appropriately regulate β‐H/C and other virulence factors in response to the environment. GBS can repress transcription of β‐H/C using the two‐component system, CovR/CovS. Recently, we described that the serine/threonine kinase Stk1 can phosphorylate CovR at threonine 65 to relieve repression of β‐H/C. In this study, we show that infection with CovR‐deficient GBS strains resulted in increased sepsis. Although CovR‐deficient GBS showed decreased ability to invade the brain endothelium in vitro, they were more proficient in induction of permeability and pro‐inflammatory signalling pathways in brain endothelium and penetration of the blood–brain barrier (BBB) in vivo. Microarray analysis revealed that CovR positively regulates its own expression and regulates the expression of 153 genes. Collectively, our results suggest that the positive feedback loop which regulates CovR transcription modulates host cell interaction and immune defence and may facilitate the transition of GBS from a commensal organism to a virulent meningeal pathogen.Keywords
This publication has 69 references indexed in Scilit:
- CsrRS Regulates Group BStreptococcusVirulence Gene Expression in Response to Environmental pH: a New Perspective on Vaccine DevelopmentJournal of Bacteriology, 2009
- Identification of Serine/Threonine Kinase Substrates in the Human Pathogen Group B StreptococcusJournal of Proteome Research, 2009
- Threonine phosphorylation prevents promoter DNA binding of the Group B Streptococcus response regulator CovRMolecular Microbiology, 2009
- Recent advances in understanding the molecular basis of group BStreptococcusvirulenceExpert Reviews in Molecular Medicine, 2008
- Signal transduction meets systems biology: deciphering specificity determinants for protein–protein interactionsMolecular Microbiology, 2008
- Positive feedback in cellular control systemsBioEssays, 2008
- Variation in the Group BStreptococcusCsrRS Regulon and Effects on PathogenicityJournal of Bacteriology, 2008
- Evaluation of the Ability of Streptococcus agalactiae Strains Isolated from Genital and Neonatal Specimens To Bind to Human Fibrinogen and Correlation with Characteristics of the fbsA and fbsB GenesInfection and Immunity, 2007
- Regulation of cytotoxin expression by converging eukaryotic‐type and two‐component signalling mechanisms in Streptococcus agalactiaeMolecular Microbiology, 2006
- Phosphorylation of the Group A Streptococcal CovR Response Regulator Causes Dimerization and Promoter-Specific Recruitment by RNA PolymeraseJournal of Bacteriology, 2006