A Brucella virulence factor targets CD11b+ macrophages triggering polyclonal B-cell activation and immune disregulation

SPERA JM; COMERCI DJ; UGALDE JE

Capital Federal

Congreso; Brucellosis 2011 International Research Conference; 2011

Asociación Argentina de Microbiología

One of the hallmarks of Brucella is its ability to establish chronic infections, indicating the existence of bacterial mechanisms capable of subverting or avoiding the ongoing immune response of the host. One common way of manipulating the immune response is by interfering with the orchestrated balance of cytokines, thus, affecting the number and function of immune effector cells. We have described a gene in Brucella abortus that codes for a protein (PrpA) with strong immunomodulatory properties. We have demonstrated that this protein is a B-cell polyclonal activator and a virulence factor, since a deletion mutant is less effective in establishing a chronic infection. To further study this novel virulence factor we have characterized the immune response elicited by the mutant compared to the wild type strain. We observed that prpA is involved in altering the number of B-cells, IgG titers, IFNg, TNFa, TGFb, IL-10 and IL-4 levels indicating that this gene is an immune regulator in vivo. In order to understand how this protein achieves this we focused on identifying the cellular target. To our surprise, although PrpA triggers a T-cell independent B-cell polyclonal proliferation, we found that PrpA binds to CD11b+ macrophages inducing the secretion of a soluble factor that promotes this proliferation. To gain insight into the molecular mechanism that triggers this response we identified, by immunoprecipitation and proteomics, a nonmuscle membrane myosin as the receptor of PrpA. Blockade of this receptor with antibodies resulted in the inhibition of binding and function of PrpA. Our results demonstrate that PrpA is a strong immunomodulator in vivo that binds to this non-canonical macrophage receptor