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 Ca2+ 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.
Highlights
Moraxella catarrhalis is one of the major respiratory pathogens in humans causing acute otitis media in children, sinusitis and laryngitis in adults as well as exacerbations in patients diagnosed with chronic obstructive pulmonary disease (COPD) [1,2]
pathogen recognition receptor (PRR) like Toll-like receptor (TLR) play an important costimulatory role in superantigen-dependent B cell activation since signaling via TLR2 and TLR9 mAb (TLR9) is required for a maximal B cell response induced by MIDexpressing bacteria [13]
B cell activation induced by Moraxella results in the production of polyclonal IgM, and these antibodies are not directed against Moraxella suggesting an important role for MID in M. catarrhalis pathogenesis [14]
Summary
Moraxella catarrhalis is one of the major respiratory pathogens in humans causing acute otitis media in children, sinusitis and laryngitis in adults as well as exacerbations in patients diagnosed with chronic obstructive pulmonary disease (COPD) [1,2]. The M. catarrhalis carriage varies during life from very high in young children to low in healthy adults. A study of pharyngeal lymphoid tissue using fluorescent in situ hybridization (FISH) has shown that 91% of the adenoids and 85% of the palatine tonsils harbour M. catarrhalis [6]. It was demonstrated that M. catarrhalis colocalizes with B cells in the outer mantel zone of the lymphoid follicles. These observations in human tonsils explain where the non-invasive pathogen M. catarrhalis may interact with B cells
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