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Bordetella bronchiseptica Modulates Macrophage Phenotype Leading to the Inhibition of CD4⁺ T Cell Proliferation and the Initiation of a Th17 Immune Response¹

Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (AI049346) and the Phillip Morris Research Management Group.

² Address correspondence and reprint requests to Dr. Ming Yuk, 201C Johnson Pavillion, 3610 Hamilton Walk, Philadelphia, PA 19104. E-mail address: mingy{at}mail.med.upenn.edu

³ Abbreviations used in this paper: TTSS, type III secretion system; ACT, adenylate cyclase toxin; BMM, bone marrow-derived macrophages; BMDC, bone marrow-derived dendritic cells; WT, wild type; HK, heat killed; MOI, multiplicity of infection.

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