title: Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytic cells via a CD14-dependent pathway distinct from that used by lipopolysaccharide.
abstract: Lipoproteins of Treponema pallidum and Borrelia burgdorferi possess potent proinflammatory properties and, thus, have been implicated as major proinflammatory agonists in syphilis and Lyme disease. Here we used purified B. burgdorferi outer surface protein A (OspA) and synthetic lipopeptides corresponding to the N-termini of OspA and the 47-kDa major lipoprotein immunogen of T. pallidum to clarify the contribution of CD14 to monocytic cell activation by spirochetal lipoproteins and lipopeptides. As with LPS, mouse anti-human CD14 Abs blocked the activation of 1,25-dihydroxyvitamin D3-matured human myelomonocytic THP-1 cells by OspA and the two lipopeptides. The existence of a CD14-dependent pathway was corroborated by using undifferentiated THP-1 cells transfected with CD14 and peritoneal macrophages from CD14-deficient BALB/c mice. Unlike LPS, cell activation by lipoproteins and lipopeptides was serum independent and was not augmented by exogenous LPS-binding protein. Two observations constituted evidence that LPS and lipoprotein/lipopeptide signaling proceed via distinct transducing elements downstream of CD14: 1) CHO cells transfected with CD14 were exquisitely sensitive to LPS but were lipoprotein/lipopeptide nonresponsive; and 2) substoichiometric amounts of deacylated LPS that block LPS signaling at a site distal to CD14 failed to antagonize activation by lipoproteins and lipopeptides. The combined results demonstrate that spirochetal lipoproteins and lipopeptides use a CD14-dependent pathway that differs in at least two fundamental respects from the well-characterized LPS recognition pathway.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Sellati
authors.forename: D A
authors.initials: DA
authors.lastname: Bouis
authors.forename: R L
authors.initials: RL
authors.lastname: Kitchens
authors.forename: R P
authors.initials: RP
authors.lastname: Darveau
authors.forename: J
authors.initials: J
authors.lastname: Pugin
authors.forename: R J
authors.initials: RJ
authors.lastname: Ulevitch
authors.forename: S C
authors.initials: SC
authors.lastname: Gangloff
authors.forename: S M
authors.initials: SM
authors.lastname: Goyert
authors.forename: M V
authors.initials: MV
authors.lastname: Norgard
authors.forename: J D
authors.initials: JD
authors.lastname: Radolf
mesh_terms: D000209:Acute-Phase Proteins; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001426:Bacterial Proteins / Q000494:pharmacology; D015748:Borrelia burgdorferi Group / Q000276:immunology*; D002352:Carrier Proteins / Q000097:blood / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002762:Cholecalciferol / Q000494:pharmacology; D005260:Female; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D008074:Lipoproteins / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D014210:Treponema pallidum / Q000276:immunology*; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D019138:Antibodies, Blocking; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002762:Cholecalciferol; D007106:Immune Sera; D007166:Immunosuppressive Agents; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010455:Peptides; D000099231:Lipopolysaccharide-Binding Protein