title: Pathogenesis of Streptococcus urinary tract infection depends on bacterial strain and β-hemolysin/cytolysin that mediates cytotoxicity, cytokine synthesis, inflammation and virulence.
abstract: Streptococcus agalactiae can cause urinary tract infection (UTI) including cystitis and asymptomatic bacteriuria (ABU). The early host-pathogen interactions that occur during S. agalactiae UTI and subsequent mechanisms of disease pathogenesis are poorly defined. Here, we define the early interactions between human bladder urothelial cells, monocyte-derived macrophages, and mouse bladder using uropathogenic S. agalactiae (UPSA) 807 and ABU-causing S. agalactiae (ABSA) 834 strains. UPSA 807 adhered, invaded and killed bladder urothelial cells more efficiently compared to ABSA 834 via mechanisms including low-level caspase-3 activation, and cytolysis, according to lactate dehydrogenase release measures and cell viability. Severe UPSA 807-induced cytotoxicity was mediated entirely by the bacterial β-hemolysin/cytolysin (β-H/C) because an β-H/C-deficient UPSA 807 isogenic mutant, UPSA 807ΔcylE, was not cytotoxic in vitro; the mutant was also significantly attenuated for colonization in the bladder in vivo. Analysis of infection-induced cytokines, including IL-8, IL-1β, IL-6 and TNF-α in vitro and in vivo revealed that cytokine and chemokine responses were dependent on expression of β-H/C that also elicited severe bladder neutrophilia. Thus, virulence of UPSA 807 encompasses adhesion to, invasion of and killing of bladder cells, pro-inflammatory cytokine/chemokine responses that elicit neutrophil infiltration, and β-H/C-mediated subversion of innate immune-mediated bacterial clearance from the bladder.
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Parklands 4222, Australia.|Research and Development Center, Ezequiel Dias Foundation (Funed), Belo Horizonte, MG, Brazil.
authors.forename: Sophie Y
authors.initials: SY
authors.lastname: Leclercq
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Parklands 4222, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sullivan
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Parklands 4222, Australia.
authors.forename: Deepak S
authors.initials: DS
authors.lastname: Ipe
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Parklands 4222, Australia.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Smith
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Parklands 4222, Australia.
authors.forename: Allan W
authors.initials: AW
authors.lastname: Cripps
authors.affiliation: School of Medical Science, and Menzies Health Institute Queensland, Griffith University, Parklands 4222, Australia.
authors.forename: Glen C
authors.initials: GC
authors.lastname: Ulett
mesh_terms: D001422:Bacterial Adhesion / Q000235:genetics / Q000502:physiology; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology*; D015373:Bacterial Typing Techniques; D001437:Bacteriuria / Q000382:microbiology*; D053148:Caspase 3 / Q000502:physiology; D003556:Cystitis / Q000382:microbiology; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D005260:Female; D006460:Hemolysin Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006461:Hemolysis; D006801:Humans; D007249:Inflammation; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008875:Middle Aged; D020556:Neutrophil Infiltration; D013045:Species Specificity; D013290:Streptococcal Infections / Q000382:microbiology*; D013292:Streptococcus agalactiae / Q000145:classification / Q000302:isolation & purification / Q000472:pathogenicity*; D020298:U937 Cells / Q000382:microbiology; D014552:Urinary Tract Infections / Q000382:microbiology*; D019459:Urothelium / Q000382:microbiology; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D006460:Hemolysin Proteins; C071495:streptococcal group B hemolysin; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; D053148:Caspase 3