title: 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.
abstract: 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.
authors.affiliation: Istituto Superiore di Sanità, Department of Infectious, Parasitic, and Immune-Mediated Diseases, Rome, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Spensieri
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fedele
authors.forename: Cecilia
authors.initials: C
authors.lastname: Fazio
authors.forename: Maria
authors.initials: M
authors.lastname: Nasso
authors.forename: Paola
authors.initials: P
authors.lastname: Stefanelli
authors.forename: Paola
authors.initials: P
authors.lastname: Mastrantonio
authors.forename: Clara Maria
authors.initials: CM
authors.lastname: Ausiello
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000502:physiology*; D001886:Bordetella pertussis / Q000472:pathogenicity*; D016764:Cell Polarity; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics; D016899:Interferon-beta / Q000235:genetics; D018664:Interleukin-12 / Q000037:antagonists & inhibitors*; D053765:Interleukin-12 Subunit p35; D009000:Monocytes / Q000166:cytology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors*; D018417:Th1 Cells / Q000502:physiology; D000099185:Interferon Regulatory Factor-8
chemical_list: D037361:Adenylate Cyclase Toxin; D000242:Cyclic AMP; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D018664:Interleukin-12; D053765:Interleukin-12 Subunit p35; D021122:Protein Subunits; D000099185:Interferon Regulatory Factor-8; C508858:IL12A protein, human