title: Cyclic AMP-mediated suppression of neutrophil extracellular trap formation and apoptosis by the Bordetella pertussis adenylate cyclase toxin.
abstract: The adenylate cyclase toxin (ACT) of Bordetella pertussis intoxicates target cells by generating supraphysiologic levels of intracellular cyclic AMP (cAMP). Since ACT kills macrophages rapidly and potently, we asked whether ACT would also kill neutrophils. In fact, ACT prolongs the neutrophil life span by inhibiting constitutive apoptosis and preventing apoptosis induced by exposure to live B. pertussis. Imaging of B. pertussis-exposed neutrophils revealed that B. pertussis lacking ACT induces formation of neutrophil extracellular traps (NETs), whereas wild-type B. pertussis does not, suggesting that ACT suppresses NET formation. Indeed, ACT inhibits formation of NETs by generating cAMP and consequently inhibiting the oxidative burst. Convalescent-phase serum from humans following clinical pertussis blocks the ACT-mediated suppression of NET formation. These studies provide novel insight into the phagocyte impotence caused by ACT, which not only impairs neutrophil function but also inhibits death of neutrophils by apoptosis and NETosis.
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA jce4u@virginia.edu.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Eby
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Gray
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Hewlett
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000378:metabolism*; D017209:Apoptosis; D001886:Bordetella pertussis / Q000276:immunology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D065206:Extracellular Traps / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D037361:Adenylate Cyclase Toxin; D000242:Cyclic AMP