Bordetella bronchiseptica Modulates Macrophage Phenotype Leading to the Inhibition of CD4+ T Cell Proliferation and the Initiation of a Th17 Immune Response

Abstract

Bordetella bronchiseptica is a Gram-negative bacterium equipped with several colonization factors that allow it to establish a persistent infection of the murine respiratory tract. Previous studies indicate that B. bronchiseptica adenylate cyclase toxin (ACT) and the type III secretion system (TTSS) synergize to drive dendritic cells into an altered phenotype to down-regulate the host immune response. In this study, we examined the effects of B. bronchiseptica ACT and TTSS on murine bone marrow-derived macrophages. We demonstrate that ACT and TTSS are required for the inhibition of Ag-driven CD4+ T cell proliferation by bacteria-infected macrophages. We identify PGE2 as the mediator of this inhibition, and we show that ACT and the TTSS synergize to increase macrophage production of PGE2. We further demonstrate that B. bronchiseptica can modulate normal macrophage function and drive the immune response toward a Th17 phenotype classified by the significant production of IL-17. In this study, we show that B. bronchiseptica-infected macrophages can induce IL-17 production from naive CD4+ splenocytes, and that lung tissues from B. bronchiseptica-infected mice exhibit a strong Th17 immune response. ACT inhibited surface expression of CD40 and CD86, suppressed TNF-α production, and up-regulated IL-6 production. TTSS also synergized with ACT to up-regulate IL-10 and PGE2 secretion. These findings indicate that persistent colonization by B. bronchiseptica may rely on the ability of the bacteria to differentially modulate both macrophage and dendritic cell function leading to an altered adaptive immune response and subsequent bacterial colonization.

Lipopolysaccharides from Bordetella pertussis and Bordetella parapertussis Differently Modulate Human Dendritic Cell Functions Resulting in Divergent Prevalence of Th17-Polarized Responses

“…These data are also in agreement with that obtained in mice, in which vaccination with a whole cell pertussis vaccine, known to contain LOS in high concentration, promotes the expansion of IL-17-producing T cells dependent on TLR4 signaling, as well as expansion of Th1 cells (48). It has also been shown that B. bronchiseptica induces a strong Th17 immune response both in vitro and in vivo (40). IL-17-producing T cells may determine in patients a sustained inflammation of the airways causing cough, as reported for other respiratory infections (49).…”

“…We have previously demonstrated that incubation of human MDDC with B. pertussis induced a Th1 predominant polarization and expression of IL-23, involved in Th17 cell expansion, in the absence of the Th1-inducing cytokine IL-12p70 (21,22). Furthermore, evidence is accumulating to show that Bordetella infection might bias the host response toward a Th17 response (40,41). In this study, novel data support this view.…”

Th17 Cells Are the Dominant T Cell Subtype Primed by Shigella flexneri Mediating Protective Immunity

“…Indeed, the priming of Ag-specific Th17 cells and/or Ag-induced IL-17A production of isolated effector cells has been reported for many pathogens, including intra-and extracellular bacteria, fungi, viruses and parasites, but in most cases the Th17/IL-17A response does not exceed the Th1/IFN-g response (22)(23)(24)(25)(32)(33)(34). It has been suggested that intestinal Citrobacter rodentium and pulmonary Bordetella bronchiseptica infections induce a dominant Th17 cell response, but this has been observed after nonspecific restimulation with PMA/ionomycin (35) or the cellular source of IL-17A has not been defined (36).…”

Intranasal Immunization Promotes Th17 Immune Responses

“…immunization has important implications in the context of optimizing rational vaccine design. However, it is critical to consider that there are also reports showing a negative influence of IL-17 on the outcome of immune responses (23). Therefore, it would be essential to carefully evaluate and weight both advantages and potential risks on a case-by-case basis.…”