title: B cell activation by outer membrane vesicles--a novel virulence mechanism.
abstract: Secretion of outer membrane vesicles (OMV) is an intriguing phenomenon of Gram-negative bacteria and has been suggested to play a role as virulence factors. The respiratory pathogens Moraxella catarrhalis reside in tonsils adjacent to B cells, and we have previously shown that M. catarrhalis induce a T cell independent B cell response by the immunoglobulin (Ig) D-binding superantigen MID. Here we demonstrate that Moraxella are endocytosed and killed by human tonsillar B cells, whereas OMV have the potential to interact and activate B cells leading to bacterial rescue. The B cell response induced by OMV begins with IgD B cell receptor (BCR) clustering and Ca(2+) mobilization followed by BCR internalization. In addition to IgD BCR, TLR9 and TLR2 were found to colocalize in lipid raft motifs after exposure to OMV. Two components of the OMV, i.e., MID and unmethylated CpG-DNA motifs, were found to be critical for B cell activation. OMV containing MID bound to and activated tonsillar CD19(+) IgD(+) lymphocytes resulting in IL-6 and IgM production in addition to increased surface marker density (HLA-DR, CD45, CD64, and CD86), whereas MID-deficient OMV failed to induce B cell activation. DNA associated with OMV induced full B cell activation by signaling through TLR9. Importantly, this concept was verified in vivo, as OMV equipped with MID and DNA were found in a 9-year old patient suffering from Moraxella sinusitis. In conclusion, Moraxella avoid direct interaction with host B cells by redirecting the adaptive humoral immune response using its superantigen-bearing OMV as decoys.
authors.affiliation: Medical Microbiology, Department of Laboratory Medicine, University Hospital Malmö, Lund University, Malmö, Sweden.
authors.forename: Maria Laura A Perez
authors.initials: ML
authors.lastname: Vidakovics
authors.forename: Johan
authors.initials: J
authors.lastname: Jendholm
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Anne
authors.initials: A
authors.lastname: Månsson
authors.forename: Christer
authors.initials: C
authors.lastname: Larsson
authors.forename: Lars-Olaf
authors.initials: LO
authors.lastname: Cardell
authors.forename: Kristian
authors.initials: K
authors.lastname: Riesbeck
mesh_terms: D018829:Adhesins, Bacterial / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands / Q000276:immunology*; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007072:Immunoglobulin D / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D001936:Moraxella catarrhalis / Q000276:immunology / Q000472:pathogenicity*; D045828:Moraxellaceae Infections / Q000276:immunology; D014066:Palatine Tonsil / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D012852:Sinusitis / Q000276:immunology / Q000382:microbiology; D014774:Virulence
chemical_list: D018829:Adhesins, Bacterial; C439616:IgD-binding protein MID, Moraxella catarrhalis; D007072:Immunoglobulin D; D011947:Receptors, Antigen, B-Cell