title: Toll-like receptor 2 participates in mediation of immune response in experimental pneumococcal meningitis.
abstract: Heterologous expression of Toll-like receptor (TLR)2 and CD14 in Chinese hamster ovary fibroblasts was reported to confer responsiveness to pneumococcal peptidoglycan. The present study characterized the role of TLR2 in the host immune response and clinical course of pneumococcal meningitis. Pneumococcal infection of mice caused a significant increase in brain TLR2 mRNA expression at both 4 and 24 h postchallenge. Mice with a targeted disruption of the TLR2 gene (TLR2-/-) showed a moderate increase in disease severity, as evidenced by an aggravation of meningitis-induced intracranial complications, a more pronounced reduction in body weight and temperature, and a deterioration of motor impairment. These symptoms were associated with significantly higher cerebellar and blood bacterial titers. Brain expression of the complement inhibitor complement receptor-related protein y was significantly higher in infected TLR2-/- than in wild-type mice, while the expression of the meningitis-relevant inflammatory mediators IL-1beta, TNF-alpha, IL-6, macrophage-inflammatory protein (MIP)-2, inducible NO synthase, and C3 was similar in both genotypes. We first ectopically expressed single candidate receptors in HEK293 cells and then applied peritoneal macrophages from mice lacking TLR2 and/or functional TLR4 for further analysis. Overexpression of TLR2 and TLR4/MD-2 conferred activation of NF-kappaB in response to pneumococcal exposure. However, pneumococci-induced TNF-alpha release from peritoneal macrophages of wild-type and TLR2/functional TLR4/double-deficient mice did not differ. Thus, while TLR2 plays a significant role in vivo, yet undefined pattern recognition receptors contribute to the recognition of and initiation of the host immune defense toward Streptococcus pneumoniae infection.
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Koedel
authors.forename: Barbara
authors.initials: B
authors.lastname: Angele
authors.forename: Tobias
authors.initials: T
authors.lastname: Rupprecht
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Andreas
authors.initials: A
authors.lastname: Roggenkamp
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Pfister
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000235:genetics / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002531:Cerebellum / Q000276:immunology / Q000382:microbiology; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007427:Intracranial Pressure / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008586:Meningitis, Pneumococcal / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000254:growth & development / Q000276:immunology; D013346:Subarachnoid Space / Q000276:immunology / Q000473:pathology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors