Suppression of T lymphocyte activation and chemotaxis by the adenylate cyclase toxin of Bordetella pertussis

Department of Evolutionary Biology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; Department of Biomedical Sciences, University of Padua, Via Trieste 75, 35121 Padua, Italy; Department of Internal Medicine and Immunoallergology, University of Florence, Viale Morgagni 85, 50134 Florence, Italy; CNRS URA 2185, Department of Structural Biology and Chemistry, Institut Pasteur, 75724 Paris Cedex 15, France

^* To whom correspondence should be addressed. Email: baldari{at}unisi.it.

	Abstract

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 cAMP production in peripheral blood lymphocytes. Treatment with CyaA resulted in a 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/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 an inhibition of the activation of MAP kinases, highlighting the ubiquitous and evolutionarily conserved MAP kinase modules as common targets of the PKA mediated immunosuppressant activities of CyaA and underlining the potential of cAMP elevating toxins as a means of immune evasion by bacterial pathogens.