title: Regulation of CovR expression in Group B Streptococcus impacts blood-brain barrier penetration.
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 beta-haemolysin/cytolysin (beta-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 beta-H/C and other virulence factors in response to the environment. GBS can repress transcription of beta-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 beta-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.
authors.affiliation: Department of Pediatric Infectious Diseases, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lembo
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gurney
authors.forename: Kellie
authors.initials: K
authors.lastname: Burnside
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
authors.forename: Melissa
authors.initials: M
authors.lastname: de los Reyes
authors.forename: James E
authors.initials: JE
authors.lastname: Connelly
authors.forename: Wan-Jung
authors.initials: WJ
authors.lastname: Lin
authors.forename: Kelsea A
authors.initials: KA
authors.lastname: Jewell
authors.forename: Anthony
authors.initials: A
authors.lastname: Vo
authors.forename: Christian W
authors.initials: CW
authors.lastname: Renken
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Doran
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rajagopal
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000382:microbiology*; D002460:Cell Line; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011499:Protein Processing, Post-Translational; D012329:RNA, Bacterial / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000382:microbiology; D013290:Streptococcal Infections / Q000382:microbiology*; D013292:Streptococcus agalactiae / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D012329:RNA, Bacterial; D012097:Repressor Proteins; D037521:Virulence Factors