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 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.

Membrane Vesicle Release in Bacteria, Eukaryotes, and Archaea: a Conserved yet Underappreciated Aspect of Microbial Life

“…4F) (references 4, 11, 14, 45, 70, 84, 92, 94 and unpublished observations). In addition, recent evidence suggests that MVs may act as antigen "decoys" in vivo to redirect the antibody response, resulting in the production of antibodies ineffective for clearance of intact organisms (93). The observations that MVs are produced in vivo during infection and that sera from patients following bacterial and fungal infections display reactivity to antigens contained in MVs (1,11,75) suggest that proteins and carbohydrates present in MVs may act as additional and po-tentially significant sources of antigen during infection beyond that provided by the intact organism itself.…”

Biogenesis of Outer Membrane Vesicles in Serratia marcescens Is Thermoregulated and Can Be Induced by Activation of the Rcs Phosphorelay System

“…Unlike the traditional, highly characterized type I to VI secretion systems, OMVs have the capacity to transport a mixture of soluble and insoluble material, which may be advantageous to the bacteria by protecting their cargo from proteases or by allowing for the assembly of multivalent complexes. Once released from bacteria, the vesicles are free to interact with the host, with considerable evidence that OMVs can be internalized into host cells (9,16,31) and have a role in modulating the host immune response (4,49,54,61).…”

Vigorous Response of Human Innate Functioning IgM Memory B Cells upon Infection by Neisseria gonorrhoeae

“…However, unexpectedly, even after 44 h of infection, some B cells did not associate with gonococci, suggesting that binding may be restricted to a specific subpopulation of cells. Moreover, no recruitment of BCR to sites of bacterial attachment was evident, indicating that this association is independent of BCR clustering, a strategy used by other bacteria (26).…”

“…Neisserial activation of B cells does not occur via BCR clustering, such as that which occurs with the Moraxella catarrhalis superantigen Moraxella IgD-binding protein (26). To date, bacterial products such as capsular polysaccharide vaccines (28,52), and purified CpG DNA (30) have been shown to expand the population of human peripheral blood IgM memory B cells.…”