A Novel Mechanism Of B Cell Activation By Bacteria

The bacterial species Burkholderia ambifaria belongs to the Burkholderia cepacia complex, a group of related bacterial strains, which can cause opportunistic infections in immunocompromised hosts. These bacteria produce various virulence factors, among which are soluble carbohydrate-binding proteins, so-called lectins. The lectin BambL from Burkholderia ambifaria binds to the carbohydrate fucose with high affinity.

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Fucose residues are found on various cell surface receptors, for example on the B cell antigen receptor (BCR). This receptor is expressed on B lymphocytes. It consists of two heavy and light chain (HC and LC) molecules, which form the constant and variable regions.

The variable region binds specific antigens with high affinity, the constant region is non-covalently associated with the Igα/Igβ heterodimer, the signal-transducing subunit of the BCR. The constant region furthermore carries carbohydrate residues including fucose. Binding of an antigen to the BCR triggers a signaling cascade downstream of the BCR resulting in B cell activation, their subsequent maturation to plasma cells, and production of large amounts of specific antibodies.

We found that BambL bound to fucosylated epitopes of the BCR thereby activating B cells in vitro. As a read-out for activation, we measured intracellular calcium influx by flow cytometry. Activation was only possible in B cells with an intact surface BCR and its proximal signaling machinery: B cells with genetically inactivated HC, as well as B cells lacking the BCR co-receptor CD19 and the spleen tyrosine kinase (Syk) could not mobilize calcium. Furthermore, prolonged stimulation with BambL led to rapid B cell death, which could be partially averted by the cytokine BAFF.

In vivo, BambL injection resulted in a rapid cellular immune response, characterized by splenomegaly, accumulation of mature follicular B cells and innate immune cells in the spleen. Simultaneously, we observed a depletion of B cells from the bone marrow. On the one hand, we assumed that the accumulation of B cells in the spleen was a result of hyperproliferation of the mature follicular B cells population. On the other hand, the absence of B cells from the bone marrow was most likely due to enhanced programmed cell death at progenitor B cell stage.

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Note that in vivo, this phenotype was BCR-independent: mice with Igα-deficient B cells that lack surface BCR expression, exhibited a similar phenotype as wild type mice. The phenotype subsided within a week in healthy animals. We hypothesized that immunocompromised patients may be unable to mount such a rapid and effective response to pathogenic particles.

We uncovered a novel mechanism of B cell activation by glycan-targeting bacterial lectins. Therefore, our study opens up the possibility for further in-depth research of host-pathogen interactions.

These findings are described in the article entitled Carbohydrate-dependent B cell activation by fucose-binding bacterial lectins, recently published in the journal Science Signaling.

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