title: Effect of the Streptococcus agalactiae Virulence Regulator CovR on the Pathogenesis of Urinary Tract Infection.
abstract: Streptococcus agalactiae can cause urinary tract infection (UTI). The role of the S. agalactiae global virulence regulator, CovR, in UTI pathogenesis is unknown.
  
  
  
  We used murine and human bladder uroepithelial cell models of UTI and S. agalactiae mutants in covR and related factors, including β-hemolysin/cytolysin (β-h/c), surface-anchored adhesin HvgA, and capsule to study the role of CovR in UTI.
  
  
  
  We found that covR-deficient serotype III S. agalactiae 874391 was significantly attenuated for colonization in mice and adhesion to uroepithelial cells. Mice infected with covR-deficient S. agalactiae produced less proinflammatory cytokines than those infected with wild-type 874391. Acute cytotoxicity in uroepithelial cells triggered by covR-deficient but not wild-type 874391 was associated with significant caspase 3 activation. Mechanistically, covR mutation significantly altered the expression of several genes in S. agalactiae 874391 that encode key virulence factors, including β-h/c and HvgA, but not capsule. Subsequent mutational analyses revealed that HvgA and capsule, but not the β-h/c, exerted significant effects on colonization of the murine urinary tract in vivo.
  
  
  
  S. agalactiae CovR promotes bladder infection and inflammation, as well as adhesion to and viability of uroepithelial cells. The pathogenesis of S. agalactiae UTI is complex, multifactorial, and influenced by virulence effects of CovR, HvgA, and capsule.
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sullivan
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.|Research and Development Center, Ezequiel Dias Foundation (FUNED), Belo Horizonte, Brazil.
authors.forename: Sophie Y
authors.initials: SY
authors.lastname: Leclercq
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
authors.forename: Deepak S
authors.initials: DS
authors.lastname: Ipe
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Carey
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Smith
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.|School of Biological Sciences, University of East Anglia, Norwich Research Park, United Kingdom.
authors.forename: Nathan
authors.initials: N
authors.lastname: Voller
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
authors.forename: Allan W
authors.initials: AW
authors.lastname: Cripps
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.
authors.forename: Glen C
authors.initials: GC
authors.lastname: Ulett
mesh_terms: D018829:Adhesins, Bacterial / Q000502:physiology; D000818:Animals; D001422:Bacterial Adhesion; D016667:Bacterial Capsules / Q000502:physiology; D001426:Bacterial Proteins / Q000502:physiology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D013292:Streptococcus agalactiae / Q000472:pathogenicity*; D001743:Urinary Bladder / Q000378:metabolism; D014552:Urinary Tract Infections / Q000382:microbiology*; D019459:Urothelium / Q000382:microbiology; D037521:Virulence Factors / Q000502:physiology*
chemical_list: D018829:Adhesins, Bacterial; D001426:Bacterial Proteins; C000619936:CovR protein, Streptococcus agalactiae; D016207:Cytokines; C559207:HvgA protein, Streptococcus agalactiae ST-17; D037521:Virulence Factors
keywords: Streptococcus agalactiae; Urinary tract infection; bladder; covR; uroepithelium; virulence