title: Bacterial pore-forming cytolysins induce neuronal damage in a rat model of neonatal meningitis.
abstract: BACKGROUND
  Group B Streptococcus (GBS) and Streptococcus pneumoniae (SP) are leading causes of bacterial meningitis in neonates and children. Each pathogen produces a pore-forming cytolytic toxin, β-hemolysin/cytolysin (β-h/c) by GBS and pneumolysin by SP. The aim of this study was to understand the role of these pore-forming cytotoxins, in particular of the GBS β-h/c, as potential neurotoxins in experimental neonatal meningitis.
  
  
  METHODS
  Meningitis was induced in 7- and 11-day-old rats by intracisternal injection of wild type (WT) GBS or SP and compared with isogenic β-h/c- or pneumolysin-deficient mutants, or a double mutant of SP deficient in pneumolysin and hydrogen peroxide production.
  
  
  RESULTS
  GBS β-h/c and SP pneumolysin contributed to neuronal damage, worsened clinical outcome and weight loss, but had no influence on the early kinetics of leukocyte influx and bacterial growth in the cerebrospinal fluid. In vitro, β-h/c-induced neuronal apoptosis occurred independently of caspase-activation and was not preventable by the broad spectrum caspase-inhibitor z-VAD-fmk.
  
  
  CONCLUSIONS
  These data suggest that both cytolytic toxins, the GBS β-h/c and SP pneumolysin, contribute to neuronal damage in meningitis and extend the concept of a key role for bacterial pore-forming cytolysins in the pathogenesis and sequelae of neonatal meningitis.
authors.affiliation: Department of Neonatology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Reiss
authors.forename: Johann S
authors.initials: JS
authors.lastname: Braun
authors.forename: Katja
authors.initials: K
authors.lastname: Jäger
authors.forename: Dorette
authors.initials: D
authors.lastname: Freyer
authors.forename: Gregor
authors.initials: G
authors.lastname: Laube
authors.forename: Christoph
authors.initials: C
authors.lastname: Bührer
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Müser
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Joerg R
authors.initials: JR
authors.lastname: Weber
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003603:Cytotoxins / Q000378:metabolism / Q000633:toxicity*; D004622:Embryo, Mammalian; D008581:Meningitis / Q000382:microbiology* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013290:Streptococcal Infections / Q000382:microbiology* / Q000473:pathology*; D013292:Streptococcus agalactiae / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000378:metabolism
chemical_list: D003603:Cytotoxins; D052899:Pore Forming Cytotoxic Proteins; D020169:Caspases