Adenylate cyclase toxin (CyaA) is released in the course of B. pertussis infection in the host's respiratory tract in order to suppress its early innate and subsequent adaptive immune defense. CD11b-expressing dendritic cells (DC), macrophages and neutrophils are professional phagocytes and key players of the innate immune system that provide a first line of defense against invading pathogens. Recent findings revealed the capacity of B. pertussis CyaA to intoxicate DC with high concentrations of 3',5'-cyclic adenosine monophosphate (cAMP), which ultimately skews the host immune response towards the expansion of Th17 cells and regulatory T cells. CyaA-induced cAMP signaling swiftly incapacitates opsonophagocytosis, oxidative burst and NO-mediated killing of bacteria by neutrophils and macrophages. The subversion of host immune responses by CyaA after delivery into DC, macrophages and neutrophils is the subject of this review.

• Keywords
• T-helper cells, immune response, intracellular pathways, phagocytosis,
• MeSH
• Adenylate Cyclase Toxin immunology   MeSH
• Cyclic AMP chemistry   MeSH
• Bordetella pertussis MeSH
• Immunity, Cellular MeSH
• Dendritic Cells immunology   MeSH
• Respiratory System immunology   microbiology   MeSH
• Phagocytosis MeSH
• Host-Pathogen Interactions MeSH
• Humans MeSH
• Macrophages immunology   MeSH
• Neutrophils immunology   MeSH
• Whooping Cough immunology   MeSH
• T-Lymphocytes, Regulatory immunology   MeSH
• Signal Transduction MeSH
• Immunity, Mucosal MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Adenylate Cyclase Toxin MeSH
• Cyclic AMP MeSH

The adenylate cyclase toxin-hemolysin (CyaA) of Bordetella pertussis is a bi-functional leukotoxin. It penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into their cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, ~1300 residue-long RTX hemolysin moiety of CyaA forms cation-selective pores and permeabilizes target cell membrane for efflux of cytosolic potassium ions. The non-enzymatic CyaA-AC(-) toxoid, has repeatedly been successfully exploited as an antigen delivery tool for stimulation of adaptive T-cell immune responses. We show that the pore-forming activity confers on the CyaA-AC(-) toxoid a capacity to trigger Toll-like receptor and inflammasome signaling-independent maturation of CD11b-expressing dendritic cells (DC). The DC maturation-inducing potency of mutant toxoid variants in vitro reflected their specifically enhanced or reduced pore-forming activity and K(+) efflux. The toxoid-induced in vitro phenotypic maturation of DC involved the activity of mitogen activated protein kinases p38 and JNK and comprised increased expression of maturation markers, interleukin 6, chemokines KC and LIX and granulocyte-colony-stimulating factor secretion, prostaglandin E2 production and enhancement of chemotactic migration of DC. Moreover, i.v. injected toxoids induced maturation of splenic DC in function of their cell-permeabilizing capacity. Similarly, the capacity of DC to stimulate CD8(+) and CD4(+) T-cell responses in vitro and in vivo was dependent on the pore-forming activity of CyaA-AC(-). This reveals a novel self-adjuvanting capacity of the CyaA-AC(-) toxoid that is currently under clinical evaluation as a tool for delivery of immunotherapeutic anti-cancer CD8(+) T-cell vaccines into DC.

• MeSH
• Adenylate Cyclase Toxin genetics   immunology   MeSH
• Adjuvants, Immunologic genetics   MeSH
• Lymphocyte Activation * MeSH
• Cell Differentiation MeSH
• CD4-Positive T-Lymphocytes immunology   MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Cytokines metabolism   MeSH
• Pore Forming Cytotoxic Proteins genetics   immunology   MeSH
• Dendritic Cells immunology   microbiology   MeSH
• Ion Transport MeSH
• Cells, Cultured MeSH
• p38 Mitogen-Activated Protein Kinases metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Cell Membrane Permeability MeSH
• Protein Domains genetics   immunology   MeSH
• Cancer Vaccines immunology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenylate Cyclase Toxin MeSH
• Adjuvants, Immunologic MeSH
• Cytokines MeSH
• Pore Forming Cytotoxic Proteins MeSH
• p38 Mitogen-Activated Protein Kinases MeSH
• Cancer Vaccines MeSH