Cyclic AMP-mediated suppression of neutrophil extracellular trap formation and apoptosis by the Bordetella pertussis adenylate cyclase toxin

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 s...

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Bibliographic Details
Published in:Infection and immunity 2014-12, Vol.82 (12), p.5256-5269
Main Authors: Eby, Joshua C, Gray, Mary C, Hewlett, Erik L
Format: Article
Language:English
Subjects:
Adenylate Cyclase Toxin - metabolism
Apoptosis
Bordetella pertussis
Bordetella pertussis - immunology
Cells, Cultured
Cellular Microbiology: Pathogen-Host Cell Molecular Interactions
Cyclic AMP - metabolism
Extracellular Traps - metabolism
Host-Pathogen Interactions
Humans
Neutrophils - drug effects
Neutrophils - immunology
Neutrophils - metabolism
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Summary: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.
ISSN:0019-9567
1098-5522
DOI:10.1128/iai.02487-14