title: Bacterial lipoprotein induces resistance to Gram-negative sepsis in TLR4-deficient mice via enhanced bacterial clearance.
abstract: TLRs are highly conserved pathogen recognition receptors. As a result, TLR4-deficient C3H/HeJ mice are highly susceptible to Gram-negative sepsis. We have previously demonstrated that tolerance induced by bacterial lipoprotein (BLP) protects wild-type mice against polymicrobial sepsis-induced lethality. In this study, we assessed whether pretreatment of C3H/HeJ mice with BLP could induce resistance to a subsequent Gram-negative Salmonella typhimurium infection. Pretreatment with BLP resulted in a significant survival benefit in TLR4-deficient C3H/HeJ mice (p < 0.0002 vs control C3H/HeJ) after challenge with live S. typhimurium (0.25 x 10(6) CFU/mouse). This survival benefit was associated with enhanced bacterial clearance from the circulation and in the visceral organs (p < 0.05 vs control C3H/HeJ). Furthermore, pretreatment with BLP resulted in significant increases in complement receptor type 3 (CR3) and FcgammaIII/IIR expression on polymorphonuclear neutrophils (PMNs) and macrophages (p < 0.05 vs control C3H/HeJ). There was impaired bacterial recognition and phagocytosis in TLR4-deficient mice compared with wild-type mice. However, a significant augmented uptake, ingestion, and intracellular killing of S. typhimurium by PMNs and peritoneal macrophages was evident in BLP-pretreated C3H/HeJ mice (p < 0.05 vs control C3H/HeJ). An up-regulation of inducible NO synthase and increased production of intracellular NO were observed in peritoneal macrophages from BLP-pretreated C3H/HeJ mice (p < 0.05 vs control C3H/HeJ). Depletion of PMNs did not diminish the beneficial effects of BLP with regard to both animal survival and bacterial clearance. These results indicate that BLP, a TLR2 ligand, protects highly susceptible TLR4-deficient mice from Gram-negative sepsis via enhanced bacterial clearance.
authors.affiliation: Department of Academic Surgery, National University of Ireland, Cork University Hospital, Cork, Ireland.
authors.forename: Gavin C
authors.initials: GC
authors.lastname: O'Brien
authors.forename: Jiang Huai
authors.initials: JH
authors.lastname: Wang
authors.forename: H Paul
authors.initials: HP
authors.lastname: Redmond
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000008:administration & dosage*; D001770:Blood Bactericidal Activity / Q000235:genetics / Q000276:immunology; D002473:Cell Wall / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D007274:Injections, Intraperitoneal; D008074:Lipoproteins / Q000008:administration & dosage*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control*; D012486:Salmonella typhimurium / Q000254:growth & development / Q000276:immunology; D018805:Sepsis / Q000235:genetics / Q000382:microbiology* / Q000401:mortality / Q000517:prevention & control*; D013203:Staphylococcal Infections / Q000235:genetics / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D001426:Bacterial Proteins; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors