Abstract
BackgroundBacterial vectors have been proposed as novel vaccine strategies to induce strong cellular immunity. Attenuated strains of Brucella abortus comprise promising vector candidates since they have the potential to induce strong CD4+ and CD8+ T-cell mediated immune responses in the absence of excessive inflammation as observed with other Gram-negative bacteria. However, some Brucella strains interfere with the maturation of dendritic cells (DCs), which is essential for antigen-specific T-cell priming. In the present study, we investigated the interaction of human monocyte-derived DCs with the smooth attenuated B. abortus strain (S) 19, which has previously been employed successfully to vaccinate cattle.Methodology/Principal findingsWe first looked into the potential of S19 to hamper the cytokine-induced maturation of DCs; however, infected cells expressed CD25, CD40, CD80, and CD86 to a comparable extent as uninfected, cytokine-matured DCs. Furthermore, S19 activated DCs in the absence of exogeneous stimuli, enhanced the expression of HLA-ABC and HLA-DR, and was able to persist intracellularly without causing cytotoxicity. Thus, DCs provide a cellular niche for persisting brucellae in vivo as a permanent source of antigen. S19-infected DCs produced IL-12/23p40, IL-12p70, and IL-10, but not IL-23. While heat-killed bacteria also activated DCs, soluble mediators were not involved in S19-induced activation of human DCs. HEK 293 transfectants revealed cellular activation by S19 primarily through engagement of Toll-like receptor (TLR)2.Conclusions/SignificanceThus, as an immunological prerequisite for vaccine efficacy, B. abortus S19 potently infects and potently activates (most likely via TLR2) human DCs to produce Th1-promoting cytokines.
Highlights
Novel vaccine strategies for the induction of cellular immune responses are based on the use of suitable microbial shuttles, which include the genetic information encoding immunogenic epitopes of the targeted pathogen
Upon co-culture in the presence of cytokines, both infected and uninfected dendritic cells (DCs) showed up-regulated surface expression of markers typically expressed by mature DCs whereas the uninfected control cells cultured in the absence of cytokines were negative for CD25 and expressed considerably less CD40, CD80, CD83, and CD86 than cytokine-matured cells (Figure 1A)
CD25, CD80, CD83, and CD86 were significantly higher expressed by cytokine-incubated, uninfected or infected DCs than by control cells incubated in medium alone while infected and uninfected, cytokine-incubated DCs did not differ regarding the expression of these molecules (Figure S1)
Summary
Novel vaccine strategies for the induction of cellular immune responses are based on the use of suitable microbial shuttles, which include the genetic information encoding immunogenic epitopes of the targeted pathogen. Only a minority of the vaccines, was successful in inducing substantial cellular or humoral immune responses [2]. Bacterial vectors have been proposed as novel vaccine strategies to induce strong cellular immunity. Attenuated strains of Brucella abortus comprise promising vector candidates since they have the potential to induce strong CD4+ and CD8+ T-cell mediated immune responses in the absence of excessive inflammation as observed with other Gramnegative bacteria. We investigated the interaction of human monocyte-derived DCs with the smooth attenuated B. abortus strain (S) 19, which has previously been employed successfully to vaccinate cattle
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