title: A novel TLR2 agonist from Bordetella pertussis is a potent adjuvant that promotes protective immunity with an acellular pertussis vaccine.
abstract: Bordetella pertussis causes whooping cough, a severe and often lethal respiratory infection in infants. A recent resurgence of pertussis has been linked with waning or suboptimal immunity induced with acellular pertussis vaccines (Pa) that were introduced to most developed countries in the 1990s because of safety concerns around the use of whole-cell pertussis vaccines (Pw). Pa are composed of individual B. pertussis antigens absorbed to alum and promote strong antibody, T helper type 2 (Th2) and Th17 responses, but are less effective at inducing cellular immunity mediated by Th1 cells. In contrast, Pw, which include endogenous Toll-like receptor (TLR) agonists, induce Th1 as well as Th17 responses. Here we report the identification and characterization of novel TLR2-activating lipoproteins from B. pertussis. These proteins contain a characteristic N-terminal signal peptide that is unique to Gram-negative bacteria and we demonstrate that one of these lipoproteins, BP1569, activates murine dendritic cells and macrophages and human mononuclear cells via TLR2. Furthermore, we demonstrated that a corresponding synthetic lipopeptide LP1569 has potent immunostimulatory and adjuvant properties, capable of enhancing Th1, Th17, and IgG2a antibody responses induced in mice with an experimental Pa that conferred superior protection against B. pertussis infection than an equivalent vaccine formulated with alum.
authors.affiliation: Molecular Immunology Group, School of Biochemistry and Immunology and Immunology Research Centre, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Dunne
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology and Immunology Research Centre, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: L A
authors.initials: LA
authors.lastname: Mielke
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology and Immunology Research Centre, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: A C
authors.initials: AC
authors.lastname: Allen
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology and Immunology Research Centre, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: C E
authors.initials: CE
authors.lastname: Sutton
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology and Immunology Research Centre, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: R
authors.initials: R
authors.lastname: Higgs
authors.affiliation: Molecular Immunology Group, School of Biochemistry and Immunology and Immunology Research Centre, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: C C
authors.initials: CC
authors.lastname: Cunningham
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology and Immunology Research Centre, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: S C
authors.initials: SC
authors.lastname: Higgins
authors.affiliation: Immune Regulation Research Group, School of Biochemistry and Immunology and Immunology Research Centre, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: K H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000595:Amino Acid Sequence; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology; D001886:Bordetella pertussis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D056724:Immunity, Humoral / Q000187:drug effects*; D008074:Lipoproteins / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D010567:Pertussis Vaccine / Q000008:administration & dosage / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D022223:Vaccines, Subunit; D014917:Whooping Cough / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D008074:Lipoproteins; D010567:Pertussis Vaccine; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D022223:Vaccines, Subunit