Bordetella Adenylate Cyclase Toxin Differentially Modulates Toll-Like Receptor-Stimulated Activation, Migration and T Cell Stimulatory Capacity of Dendritic Cells

Abstract

Adenylate cyclase toxin (CyaA) is a key virulence factor of the whooping cough agent Bordetella pertussis. The toxin targets CD11b-expressing phagocytes and delivers into their cytosol an adenylyl cyclase (AC) enzyme that subverts cellular signaling by increasing cAMP levels. In the present study, we analyzed the modulatory effects of CyaA on adhesive, migratory and antigen presenting properties of Toll-like receptor (TLR)-activated murine and human dendritic cells (DCs). cAMP signaling of CyaA enhanced TLR-induced dissolution of cell adhesive contacts and migration of DCs towards the lymph node-homing chemokines CCL19 and CCL21 in vitro. Moreover, we examined in detail the capacity of toxin-treated DCs to induce CD4+ and CD8+ T cell responses. Exposure to CyaA decreased the capacity of LPS-stimulated DCs to present soluble protein antigen to CD4+ T cells independently of modulation of co-stimulatory molecules and cytokine production, and enhanced their capacity to promote CD4+CD25+Foxp3+ T regulatory cells in vitro. In addition, CyaA decreased the capacity of LPS-stimulated DCs to induce CD8+ T cell proliferation and limited the induction of IFN-γ producing CD8+ T cells while enhancing IL-10 and IL-17-production. These results indicate that through activation of cAMP signaling, the CyaA may be mobilizing DCs impaired in T cell stimulatory capacity and arrival of such DCs into draining lymph nodes may than contribute to delay and subversion of host immune responses during B. pertussis infection.

Cyclic AMP-Elevating Capacity of Adenylate Cyclase Toxin-Hemolysin Is Sufficient for Lung Infection but Not for Full Virulence of Bordetella pertussis

“…), hence corroborate and validate our previous observations with purified recombinant CyaA. These studies showed that as little as 10 ng/ml of CyaA was able to skew the antigen-presenting capacities of LPS-activated dendritic cells toward a tolerogenic phenotype and made them expand antigen-specific Foxp3 ϩ CD25 ϩ CD4 ϩ Treg cells (54). Higher CyaA concentrations were, indeed, recently found in nasal aspirates of infants with pertussis and in nasopharyngeal washes of B. pertussis-infected baboons (12).…”

cAMP signalling ofBordetellaadenylate cyclase toxin through the SHP‐1 phosphatase activates the BimEL‐Bax pro‐apoptotic cascade in phagocytes

“…While the immediate outcome of CyaA action appears to consist in ablation of bactericidal functions of sentinel cells of host innate immunity, such as neutrophils and macrophages, action of the CyaA toxin is likely to have also longer lasting subversive effects on adaptive immune response capacities of the host. These would comprise manipulation of dendritic cell maturation and suppression of pro-inflammatory cytokine production, as well as eventual induction of apoptosis of host myeloid phagocytes (CD11b + ) upon prolonged exposure to CyaA in vivo, such as in the lungs of Bordetella pertussis-infected mice (Khelef et al, 1992;Khelef and Guiso, 1995;Boschwitz et al, 1997;Gueirard et al, 1998;Bachelet et al, 2002;Fedele et al, 2010;Adkins et al, 2014).…”

Bordetella pertussis Adenylate Cyclase Toxin Blocks Induction of Bactericidal Nitric Oxide in Macrophages through cAMP-Dependent Activation of the SHP-1 Phosphatase

“…As a result, phagocytosis and killing of complementopsonized bacteria by neutrophils and macrophages are blocked near-instantaneously (8,11,12). Moreover, CyaA/cAMP signaling also skews the TLR-triggered maturation of dendritic cells and impairs their capacity to present Ags to T cells for induction of adaptive cellular immune responses (13).…”