Suppression of T-lymphocyte activation and chemotaxis by the adenylate cyclase toxin of Bordetella pertussis.
The adenylate cyclase toxin (CyaA) released by Bordetella pertussis is an essential virulence factor for colonization of the host. This toxin inhibits migration and activation of phagocytes, thereby preventing bacterial killing. In addition, CyaA interferes with the initiation of adaptive immunity by misdirecting dendritic cell differentiation to a suppressive rather than stimulatory phenotype. Here we show that CyaA directly affects adaptive responses by catalyzing cyclic AMP (cAMP) production in peripheral blood lymphocytes. Treatment with CyaA resulted in profound impairment of T-lymphocyte activation and chemotaxis. These effects resulted from inhibition of T-cell antigen receptor and chemokine receptor signaling via a cAMP/protein kinase A (PKA)-dependent pathway. A comparison of the activities of CyaA on T-cell and macrophage activation and migration revealed that the biological effects of the toxin were paralleled by inhibition of the activation of mitogen-activated protein (MAP) kinases, highlighting the conclusion that the ubiquitous and evolutionarily conserved MAP kinase modules are common targets of the PKA-mediated immunosuppressant activities of CyaA and underlining the potential of cAMP-elevating toxins as a means of evasion of immunity by bacterial pathogens.
Paccani
Silvia Rossi
SR
Department of Evolutionary Biology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Dal Molin
Federica
F
Benagiano
Marisa
M
Ladant
Daniel
D
D'Elios
Mario M
MM
Montecucco
Cesare
C
Baldari
Cosima T
CT
D037361:Adenylate Cyclase Toxin / Q000235:genetics / Q000502:physiology / Q000633:toxicity*; D001886:Bordetella pertussis / Q000378:metabolism / Q000472:pathogenicity*; D002464:Cell Migration Inhibition; D002634:Chemotaxis, Leukocyte; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology*; D010566:Virulence Factors, Bordetella / Q000633:toxicity*
D037361:Adenylate Cyclase Toxin; D010566:Virulence Factors, Bordetella; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases