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Infection and Immunity, May 2006, p. 2831-2838, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2831-2838.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Bordetella pertussis Inhibition of Interleukin-12 (IL-12) p70 in Human Monocyte-Derived Dendritic Cells Blocks IL-12 p35 through Adenylate Cyclase Toxin-Dependent Cyclic AMP Induction

Fabiana Spensieri,{dagger} Giorgio Fedele,{dagger} Cecilia Fazio, Maria Nasso, Paola Stefanelli, Paola Mastrantonio, and Clara Maria Ausiello*

Istituto Superiore di Sanità, Department of Infectious, Parasitic, and Immune-Mediated Diseases, 00161 Rome, Italy

Received 21 November 2005/ Returned for modification 3 January 2006/ Accepted 14 February 2006

Bordetella pertussis, the causative agent of whooping cough, possesses an array of virulence factors, including adenylate cyclase toxin (ACT), relevant in the establishment of infection. Here we better define the impact of cyclic AMP (cAMP) intoxication due to the action of ACT on dendritic cell (DC)-driven immune response, by infecting monocyte-derived DC (MDDC) with an ACT-deficient B. pertussis mutant (ACT–18HS19) or its parental strain (WT18323). Both strains induced MDDC maturation and antigen-presenting cell functions; however, only ACT–18HS19 infected MDDC-induced production of interleukin-12 (IL-12) p70. Gene expression analysis of the IL-12 cytokine family subunits revealed that both strains induced high levels of p40 (protein chain communal to IL-12 p70 and IL-23) as well as p19, a subunit of IL-23. Conversely only ACT–18HS19 infection induced consistent transcription of IL-12 p35, a subunit of IL-12 p70. Addition of the cAMP analogous D-butyril-cAMP (D-cAMP) abolished IL-12 p70 production and IL-12 p35 expression in ACT–18HS19-infected MDDC. ACT–18HS19 infection induced the expression of the transcription factors interferon regulatory factor 1 (IRF-1) and IRF-8 and of beta interferon, involved in IL-12 p35 regulation, and the expression of these genes was inhibited by D-cAMP addition and in WT18323-infected MDDC. The concomitant expression of IL-12 p70 and IL-23 allowed ACT–18HS19 to trigger a more pronounced T helper 1 polarization compared to WT18323. The present study suggests that ACT-dependent cAMP induction leads to the inhibition of pathways ultimately leading to IL-12 p35 production, thus representing a mechanism for B. pertussis to escape the host immune response.

* Corresponding author. Mailing address: Istituto Superiore di Sanità, Department of Infectious, Parasitic, and Immune-Mediated Diseases, Anti-Infectious Immunity Unit, Viale Regina Elena, 299, 00161 Rome, Italy. Phone: 39 06 4990 2890. Fax: 39 06 4990 3168. E-mail: ausiello{at}iss.it.

Editor: J. B. Bliska

{dagger} F.S. and G.F. contributed equally to this study.

Infection and Immunity, May 2006, p. 2831-2838, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2831-2838.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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