B cell activation by outer membrane vesicles--a novel virulence mechanism

Area of Science:

• Immunology
• Microbiology
• Bacterial Pathogenesis

Background:

• Outer membrane vesicles (OMV) from Gram-negative bacteria, like Moraxella catarrhalis, are implicated as virulence factors.
• M. catarrhalis resides near B cells in tonsils and can induce T cell-independent B cell responses via the MID superantigen.

Purpose of the Study:

• To investigate the interaction between M. catarrhalis OMV and human tonsillar B cells.
• To elucidate the mechanisms by which OMV influence B cell activation and bacterial survival.

Main Methods:

• Endocytosis assays of M. catarrhalis by B cells.
• Analysis of B cell receptor (BCR) clustering, calcium mobilization, and internalization upon OMV exposure.
• Co-localization studies of BCR, TLR9, and TLR2 in lipid rafts.
• Assessment of B cell activation markers (IL-6, IgM, HLA-DR, CD45, CD64, CD86) in response to OMV with varying components (MID, CpG-DNA).
• In vivo verification in a patient with Moraxella sinusitis.

Main Results:

• M. catarrhalis bacteria are endocytosed and killed by B cells, but OMV can rescue bacteria by activating B cells.
• OMV induce B cell activation through IgD BCR clustering, calcium mobilization, and internalization.
• Toll-like receptors 9 and 2 (TLR9, TLR2) co-localize with BCR in lipid rafts upon OMV exposure.
• Both MID and unmethylated CpG-DNA motifs on OMV are critical for B cell activation.
• OMV containing MID activate B cells, leading to IL-6 and IgM production and increased surface marker expression.
• MID-deficient OMV fail to activate B cells, while OMV-associated DNA activates B cells via TLR9.
• In vivo findings confirmed OMV with MID and DNA in a patient with sinusitis.

Conclusions:

• Moraxella catarrhalis employs OMV as decoys to manipulate the adaptive humoral immune response.
• OMV-bound MID and CpG-DNA trigger B cell activation, promoting bacterial survival and potentially contributing to sinusitis pathogenesis.
• This mechanism allows M. catarrhalis to evade direct interaction with host B cells by hijacking their signaling pathways.