title: TLR-mediated inflammatory responses to Streptococcus pneumoniae are highly dependent on surface expression of bacterial lipoproteins.
abstract: Streptococcus pneumoniae infections induce inflammatory responses that contribute toward both disease pathogenesis and immunity, but the host-pathogen interactions that mediate these effects are poorly defined. We used the surface lipoprotein-deficient ∆lgt pneumococcal mutant strain to test the hypothesis that lipoproteins are key determinants of TLR-mediated immune responses to S. pneumoniae. We show using reporter assays that TLR2 signaling is dependent on pneumococcal lipoproteins, and that macrophage NF-κB activation and TNF-α release were reduced in response to the ∆lgt strain. Differences in TNF-α responses between Δlgt and wild-type bacteria were abrogated for macrophages from TLR2- but not TLR4-deficient mice. Transcriptional profiling of human macrophages revealed attenuated TLR2-associated responses to ∆lgt S. pneumoniae, comprising many NF-κB-regulated proinflammatory cytokine and chemokine genes. Importantly, non-TLR2-associated responses were preserved. Experiments using leukocytes from IL-1R-associated kinase-4-deficient patients and a mouse pneumonia model confirmed that proinflammatory responses were lipoprotein dependent. Our data suggest that leukocyte responses to bacterial lipoproteins are required for TLR2- and IL-1R-associated kinase-4-mediated inflammatory responses to S. pneumoniae.
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Gillian
authors.initials: G
authors.lastname: Tomlinson
authors.affiliation: Centre for Inflammation and Tissue Repair, Division of Medicine, University College Medical School, Rayne Institute, London WC1E 6JF, United Kingdom;
authors.forename: Suneeta
authors.initials: S
authors.lastname: Chimalapati
authors.affiliation: Centre for Inflammation and Tissue Repair, Division of Medicine, University College Medical School, Rayne Institute, London WC1E 6JF, United Kingdom;
authors.forename: Tracey
authors.initials: T
authors.lastname: Pollard
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Thabo
authors.initials: T
authors.lastname: Lapp
authors.affiliation: Centre for Inflammation and Tissue Repair, Division of Medicine, University College Medical School, Rayne Institute, London WC1E 6JF, United Kingdom; Infectious Diseases and Microbiology Unit, University College London Institute of Child Health, London WC1N 1Eh, United Kingdom;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cohen
authors.affiliation: Centre for Inflammation and Tissue Repair, Division of Medicine, University College Medical School, Rayne Institute, London WC1E 6JF, United Kingdom;
authors.forename: Emilie
authors.initials: E
authors.lastname: Camberlein
authors.affiliation: Centre for Inflammation and Tissue Repair, Division of Medicine, University College Medical School, Rayne Institute, London WC1E 6JF, United Kingdom;
authors.forename: Sian
authors.initials: S
authors.lastname: Stafford
authors.affiliation: Centre for Inflammation and Tissue Repair, Division of Medicine, University College Medical School, Rayne Institute, London WC1E 6JF, United Kingdom;
authors.forename: Jimstan
authors.initials: J
authors.lastname: Periselneris
authors.affiliation: Centre for Bacterial Cell Biology, Newcastle University Medical School, Newcastle upon Tyne NE2 4AX, United Kingdom;
authors.forename: Christine
authors.initials: C
authors.lastname: Aldridge
authors.affiliation: Centre for Bacterial Cell Biology, Newcastle University Medical School, Newcastle upon Tyne NE2 4AX, United Kingdom;
authors.forename: Waldemar
authors.initials: W
authors.lastname: Vollmer
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Necker Medical School, University Paris Descartes, Sorbonne Paris Cité, Paris 75015, France; Study Center for Primary Immunodeficiencies, Public Assistance-Paris Hospitals, Necker Enfants Malades Hospital, Paris 75743, France; and.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Necker Medical School, University Paris Descartes, Sorbonne Paris Cité, Paris 75015, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Mahdad
authors.initials: M
authors.lastname: Noursadeghi
authors.affiliation: Centre for Inflammation and Tissue Repair, Division of Medicine, University College Medical School, Rayne Institute, London WC1E 6JF, United Kingdom; jeremy.brown@ucl.ac.uk.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Brown
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology; D008074:Lipoproteins / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000081207:Primary Immunodeficiency Diseases; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D008074:Lipoproteins; D016328:NF-kappa B; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse