Adenylate cycalse toxin of<i>Bordetella pertussis</i>inhibits TLR-induced IRF-1 and IRF-8 activation and IL-12 production and enhances IL-10 through MAPK activation in dendritic cells

Hickey, Fionnuala B.; Brereton, Corinna F.; Mills, Kingston H. G.

doi:10.1189/jlb.0208113

Cited by 54 publications

(42 citation statements)

References 47 publications

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“…2). However, NF-kB activation alone does not lead to iNOS expression, and Hickey and coworkers (63) observed previously that cAMP production by CyaA caused a decrease of levels of both IRF1 and IRF8 transcription factors. Similarly, cAMP elevation by cholera toxin was found to cause inhibition of IRF1-IRF8 interaction (64).…”

Section: Discussionmentioning

confidence: 91%

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

Černý

Kamanová

Mašín

et al. 2015

The Journal of Immunology

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The adenylate cyclase toxin–hemolysin (CyaA) plays a key role in the virulence of Bordetella pertussis. CyaA penetrates complement receptor 3–expressing phagocytes and catalyzes uncontrolled conversion of cytosolic ATP to the key second messenger molecule cAMP. This paralyzes the capacity of neutrophils and macrophages to kill bacteria by complement-dependent oxidative burst and opsonophagocytic mechanisms. We show that cAMP signaling through the protein kinase A (PKA) pathway activates Src homology domain 2 containing protein tyrosine phosphatase (SHP) 1 and suppresses production of bactericidal NO in macrophage cells. Selective activation of PKA by the cell-permeable analog N6-benzoyladenosine-3′,5′-cyclic monophosphate interfered with LPS-induced inducible NO synthase (iNOS) expression in RAW264.7 macrophages, whereas inhibition of PKA by H-89 largely restored the production of iNOS in CyaA-treated murine macrophages. CyaA/cAMP signaling induced SHP phosphatase–dependent dephosphorylation of the c-Fos subunit of the transcription factor AP-1 and thereby inhibited TLR4-triggered induction of iNOS gene expression. Selective small interfering RNA knockdown of SHP-1, but not of the SHP-2 phosphatase, rescued production of TLR-inducible NO in toxin-treated cells. Finally, inhibition of SHP phosphatase activity by NSC87877 abrogated B. pertussis survival inside murine macrophages. These results reveal that an as yet unknown cAMP-activated signaling pathway controls SHP-1 phosphatase activity and may regulate numerous receptor signaling pathways in leukocytes. Hijacking of SHP-1 by CyaA action then enables B. pertussis to evade NO-mediated killing in sentinel cells of innate immunity.

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Section: Discussionmentioning

confidence: 91%

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

Černý

Kamanová

Mašín

et al. 2015

The Journal of Immunology

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“…It has previously been shown that CyaA-elicited signaling of the cAMP-activated protein kinase A modulates maturation and cytokine production of lipopolysaccharide (LPS)-stimulated DCs (43)(44)(45)(46)(47)(48)(49). It remained unclear, however, if the cell-permeabilizing capacity of CyaA modulates the cAMP-mediated skewing of the phenotypic maturation of DCs exposed to live B. pertussis cells.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of Bordetella pertussis targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, ␣ M ␤ 2 integrin, or CD11b/CD18). CyaA delivers into cells an N-terminal adenylyl cyclase (AC) enzyme domain that is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cyclic AMP (cAMP), a key second messenger subverting bactericidal activities of phagocytes. In parallel, the hemolysin (Hly) moiety of CyaA forms cation-selective hemolytic pores that permeabilize target cell membranes. We constructed the first B. pertussis mutant secreting a CyaA toxin having an intact capacity to deliver the AC enzyme into CD11b-expressing (CD11b ϩ ) host phagocytes but impaired in formation of cell-permeabilizing pores and defective in cAMP elevation in CD11b Ϫ cells. The nonhemolytic AC ϩ Hly Ϫ bacteria inhibited the antigen-presenting capacities of coincubated mouse dendritic cells in vitro and skewed their Toll-like receptor (TLR)-triggered maturation toward a tolerogenic phenotype. The AC ϩ Hly Ϫ mutant also infected mouse lungs as efficiently as the parental AC ϩ Hly ϩ strain. Hence, elevation of cAMP in CD11b Ϫ cells and/or the poreforming capacity of CyaA were not required for infection of mouse airways. The latter activities were, however, involved in bacterial penetration across the epithelial layer, enhanced neutrophil influx into lung parenchyma during sublethal infections, and the exacerbated lung pathology and lethality of B. pertussis infections at higher inoculation doses (Ͼ10 7 CFU/mouse). The pore-forming activity of CyaA further synergized with the cAMP-elevating activity in downregulation of major histocompatibility complex class II (MHC-II) molecules on infiltrating myeloid cells, likely contributing to immune subversion of host defenses by the whooping cough agent.KEYWORDS Bordetella pertussis, adenylate cyclase toxin-hemolysin, cAMP intoxication, lung colonization, pore-forming activity, virulence T he adenylate cyclase toxin-hemolysin is produced by all three Bordetella species pathogenic to mammals, and it plays a prominent role in the early phases of respiratory tract infection by the whooping cough agent, Bordetella pertussis (1-3). The toxin specifically binds the CD11b subunit of the complement receptor 3 (CR3) (4, 5) and exerts an array of immunosubversive and cytotoxic activities on myeloid phagocytes. CyaA delivers a cell-invasive adenylyl cyclase (AC) enzyme domain into cytosol of CD11b ϩ cells, where the AC is activated by calmodulin and converts cytosolic ATP to the signaling molecule cyclic AMP (cAMP). The generated supraphysiological levels of cAMP then nearly instantly ablate the bactericidal oxidative burst and opsonophago-

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“…Several studies have demonstrated the crucial role of p38 activation mediated in the production of Th1 cytokines, especially TNF-a (20) and IL-12 (25,26). Additionally, several reports highlighted the importance of constitutively active (phosphorylated) ERK in the survival of AMs in human lungs (27).…”

Section: Nod1/ Tlr4 Signaling Induces Erk and P38 Phosphorylation In mentioning

confidence: 99%

Dysregulation of p38 and MKP-1 in Response to NOD1/TLR4 Stimulation in Sarcoid Bronchoalveolar Cells

Rastogi¹,

Du²,

Ju³

et al. 2011

Am J Respir Crit Care Med

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Rationale: Sarcoidosis is a systemic inflammatory disorder characterized by distinct up-regulation of Th1 cytokines, such as tumor necrosis factor (TNF)-a and IL-12. The mechanism underlying this up-regulation remains unclear. Recognition of microbial moieties through Toll-like or Nod-like receptors evokes sequential activation of mitogen-activated protein kinases (MAPKs), which plays a role in Th1-immune response. Objectives: To test the hypothesis that dysregulation in MAPK signaling in response to microbial stimulation is important in mediating Th1 response in sarcoidosis. Methods: Ex vivo cultured bronchoalveolar lavage (BAL) cells isolated from patients with sarcoidosis and control subjects were stimulated with low-dose Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 1 (NOD1) ligands as a model of microbial stimulation, and MAPK signaling and inflammatory response were analyzed. Measurements and Main Results: BAL cells from patients with sarcoidosis exhibited higher basal p38 activity, greater p38 phosphorylation, and more robust production of TNF-a and IL-12/IL-23p40 on stimulation with NOD1 and TLR4 agonists than cells isolated from control subjects. In contrast, control BAL cells had greater basal extracellular signal-regulated kinase (ERK) activity and NOD1 and TLR4 agonists preferentially activated the ERK pathway. Inhibition of p38, but not ERK, attenuated production of both IL12/IL23p40 and TNF-a. Interestingly, stimulation of cells from patients with sarcoidosis with either NOD1 or TLR4 ligand failed to induce MAPK phosphatase 1 (MKP-1). Adenovirus-mediated overexpression of MKP-1 attenuated p38 activation and decreased the production of IL12/IL23p40 and TNF-a in sarcoid BAL cells. Conclusions: Our results suggest that enhanced p38 signaling in response to microbial products is caused by abnormal regulation of MKP-1 and contributes to heightened inflammation in sarcoidosis.

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Adenylate cycalse toxin ofBordetella pertussisinhibits TLR-induced IRF-1 and IRF-8 activation and IL-12 production and enhances IL-10 through MAPK activation in dendritic cells

Cited by 54 publications

References 47 publications

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

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

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

Dysregulation of p38 and MKP-1 in Response to NOD1/TLR4 Stimulation in Sarcoid Bronchoalveolar Cells

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