Brucella suisPrevents Human Dendritic Cell Maturation and Antigen Presentation through Regulation of Tumor Necrosis Factor Alpha Secretion

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Abstract
Brucellais a facultative intracellular pathogen and the etiological agent of brucellosis. In some cases, human brucellosis results in a persistent infection that may reactivate years after the initial exposure. The mechanisms by which the parasite evades clearance by the immune response to chronically infect its host are unknown. We recently demonstrated that dendritic cells (DCs), which are critical components of adaptive immunity, are highly susceptible toBrucellainfection and are a preferential niche for the development of the bacteria. Here, we report that in contrast to several intracellular bacteria,Brucellaprevented the infected DCs from engaging in their maturation process and impaired their capacities to present antigen to naïve T cells and to secrete interleukin-12. Moreover,Brucella-infected DCs failed to release tumor necrosis factor alpha (TNF-α), a defect involving the bacterial protein Omp25. Exogenous TNF-α addition toBrucella-infected DCs restored cell maturation and allowed them to present antigens. Two avirulent mutants ofB. suis,B. suis bvrRandB. suis omp25mutants, which do not express the Omp25 protein, triggered TNF-α production upon DC invasion. Cells infected with these mutants subsequently matured and acquired the ability to present antigens, two properties which were dramatically impaired by addition of anti-TNF-α antibodies. In light of these data, we propose a model in which virulentBrucellaalters the maturation and functions of DCs through Omp25-dependent control of TNF-α production. This model defines a specific evasion strategy of the bacteria by which they can escape the immune response to chronically infect their host.

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