title: Pneumococcal capsular polysaccharide is immunogenic when present on the surface of macrophages and dendritic cells: TLR4 signaling induced by a conjugate vaccine or by lipopolysaccharide is conducive.
abstract: Previously, we reported that a peptide, p458, from the sequence of the mammalian 60-kDa heat shock protein (hsp60) molecule can serve as a carrier in conjugate vaccines with capsular polysaccharide (CPS) molecules of various bacteria. These conjugate vaccines were effective injected in PBS without added adjuvants. We now report that p458 conjugated to pneumococcal CPS type 4 (PS4) manifests innate adjuvant effects: it stimulated mouse macrophages to secrete IL-12 and induced the late appearance of PS4 on the macrophage surface in a TLR4-dependent manner; PS4 alone or conjugated to other carriers did not stimulate macrophages in vitro. The injection of macrophages manifesting PS4 on the surface into mice induced long-term resistance to lethal Streptococcus pneumoniae challenge. The TLR4 ligand LPS could also induce the late appearance on the surface of unconjugated PS4 and resistance to challenge in injected mice. Resistance was not induced by macrophages containing only internalized PS4 or by pulsed macrophages that had been lysed. Glutaraldehyde-fixed macrophages pulsed with PS4 did induce resistance to lethal challenge. Moreover, bone marrow-derived dendritic cells activated by LPS and pulsed with unconjugated CPS were also effective in inducing resistance to lethal challenge. Resistance induced by the PS4-pulsed bone marrow-derived dendritic cell was specific for pneumococcal CPS serotypes (type 3 or type 4) and was associated with the induction of CPS-specific IgG and IgM Abs.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Cohen
authors.forename: Michal
authors.initials: M
authors.lastname: Stolarsky-Bennun
authors.forename: Hila
authors.initials: H
authors.lastname: Amir-Kroll
authors.forename: Raanan
authors.initials: R
authors.lastname: Margalit
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nussbaum
authors.forename: Michal
authors.initials: M
authors.lastname: Cohen-Sfady
authors.forename: Meirav
authors.initials: M
authors.lastname: Pevsner-Fischer
authors.forename: Mati
authors.initials: M
authors.lastname: Fridkin
authors.forename: Herve
authors.initials: H
authors.lastname: Bercovier
authors.forename: Lea
authors.initials: L
authors.lastname: Eisenbach
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.forename: Irun R
authors.initials: IR
authors.lastname: Cohen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000382:microbiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000382:microbiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D005260:Female; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000276:immunology*; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D022242:Pneumococcal Vaccines; D011135:Polysaccharides, Bacterial; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018074:Vaccines, Conjugate; C053136:pneumonococcal polysaccharide, type 4