title: Impact of microbial tolerance in persistent secondary Klebsiella pneumoniae peritonitis.
abstract: OBJECTIVE
  Microbial tolerance represents a diminished pro-inflammatory response following repeated stimulation by a host of pathogen-associated molecular patterns (PAMPs) of varying origins. Toll-like receptors (TLRs) have been centrally implicated in the development of tolerance. The purpose of this study was to investigate the impact of tolerance in a previously described murine model. C57BL/6 mice were pretreated intraperitoneally with phosphate buffered saline (PBS), heat-killed Klebsiella 2×10(8) CFU (hkKlebsiella), LPS 10mg/kg (LPS 10), or BLP 10mg/kg (BLP 10). Following pretreatment, peritonitis was induced 24h later using 10(3) intraperitoneal Klebsiella CFU. Peritoneal concentrations of TNF-α, IL-10 and nitric oxide (NO), as well as characteristic cell patterns, were determined. Long-term consequences of microbial tolerance were assessed by measuring survival and weight-loss.
  
  
  RESULTS
  Following in vitro stimulation with Klebsiella 10(5) and 10(3) CFU, TNF-α and IL-10 secretion were diminished in macrophages harvested from mice pretreated with hkKlebsiella, LPS 10 and BLP 10. Pretreated animals had significantly lower bacterial counts. Conversely, local NO levels were elevated. Survival was not different between the groups.
  
  
  CONCLUSIONS
  Pretreatment with TLR ligands induced microbial tolerance, with reduced peritoneal cytokine concentrations and enhanced early bacterial clearance. However, this did not translate into improved survival.
authors.affiliation: Veterans Affairs Medical Center, Louisville, KY, USA.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Lenz
authors.forename: Motaz
authors.initials: M
authors.lastname: Qadan
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Gardner
authors.forename: William G
authors.initials: WG
authors.lastname: Cheadle
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000187:drug effects; D002021:Buffers; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000276:immunology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D010529:Peritoneal Cavity / Q000382:microbiology / Q000473:pathology; D010538:Peritonitis / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D016019:Survival Analysis; D051193:Toll-Like Receptors / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D002021:Buffers; D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D009569:Nitric Oxide