Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenylate cyclase toxin (CyaA) is one of the major virulence factors produced by Bordetella pertussis, the whooping cough agent. CyaA belongs to the repeat in toxin protein family and requires a post-translational fatty acylation to form cation-selective channels in target cell membranes and to penetrate into cytosol. We have demonstrated recently that CyaA uses the alphaMbeta2 integrin (CD11b/CD18) as a specific cellular receptor. Here we show that the acylation of CyaA is required for a productive and tight interaction of the toxin with cells expressing CD11b. In addition, we demonstrate that the catalytic domain is not required for binding of CyaA to CD11b and that the main integrin interacting domain of CyaA is located in its glycine/aspartate-rich repeat region. These data decipher, for the first time, the interaction of CyaA with CD11b-positive cells and open new prospects for understanding the interaction of Bordetella pertussis with innate and adaptive immune systems.
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PMID:Interaction of Bordetella pertussis adenylate cyclase with CD11b/CD18: Role of toxin acylation and identification of the main integrin interaction domain. 1288 82

The adenylate cyclase (CyaA) of Bordetella pertussis is able to deliver CD8(+) T cell epitopes into the cytosol of CD11b(+) dendritic cells (DC) following its specific interaction with the alpha(M)beta(2) integrin (CD11b/CD18). This delivery results in intracellular processing and presentation by MHC class I molecules of the CD8(+) T cell epitopes inserted into CyaA. Indeed, we previously showed that CyaA toxins carrying a single cytotoxic T lymphocyte (CTL) epitope can induce efficient protective and therapeutic antitumor immunity in mice. With a view to elaborating cancer immunotherapy in humans using CyaA, we constructed two recombinant CyaA carrying HLA*0201-restricted melanoma epitopes. Here we show that these recombinant CyaA induce strong anti-melanoma CTL responses in HLA*0201 transgenic mice, even after a single i.v. immunization without adjuvant. These responses are long lasting, since they were also detected 5 months after the last injection. Finally, human DC treated with the recombinant CyaA were shown to process and present efficiently the melanoma epitopes to human CTL clones. Altogether, our results demonstrate that tumoral epitopes inserted into CyaA are efficiently processed and presented in association with human MHC molecules. These observations suggest that CyaA is capable of activating antitumoral CTL in humans and highlight the potential of CyaA for use in cancer immunotherapy.
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PMID:Recombinant adenylate cyclase toxin of Bordetella pertussis induces cytotoxic T lymphocyte responses against HLA*0201-restricted melanoma epitopes. 1464 51

Antineutrophil cytoplasm antibodies (ANCA) activate TNF-alpha-primed neutrophils to undergo a respiratory burst. The intracellular signals that mediate activation have not been studied extensively but could increase the understanding of the pathogenesis small vessel vasculitis. It was demonstrated that ANCA-IgG induced phosphorylation of the tyrosine kinase Syk in TNF-alpha-primed neutrophils from healthy donors. Syk was not phosphorylated in response to ANCA F(ab')(2). Furthermore, Syk phosphorylation was attenuated by blockade of both low-affinity Fcgamma receptors and CD18. Similarly, low-affinity Fcgamma receptor blockade reduced ANCA-induced superoxide production. In patient-derived neutrophils, the high-affinity Fcgamma receptor FcgammaRI was also demonstrated to be involved in ANCA-induced superoxide production. However, Syk phosphorylation was not attenuated by blockade of the FcgammaRI, present on neutrophils from vasculitis patients. The tyrosine kinase inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine inhibited the ANCA-induced respiratory burst and Syk phosphorylation, suggesting that Src kinases lie upstream of Syk activation but downstream of ANCA engagement of Fcgamma receptors. Piceatannol, another tyrosine kinase inhibitor, also inhibited ANCA-induced Syk phosphorylation and the ANCA-stimulated respiratory burst, supporting the proposed functional role for Syk in ANCA signaling. ANCA-induced phosphorylation of Cbl and intracellular calcium transients, potential downstream mediators of Syk activation, were also blocked by tyrosine kinase inhibitors. While it has previously been shown that pertussis toxin diminishes the ANCA-induced respiratory burst, indicating heterotrimeric G protein involvement, Syk phosphorylation and calcium transients were unaffected by pertussis toxin. Collectively, these data show that Syk phosphorylation is induced during ANCA-triggered neutrophil activation.
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PMID:Activation of Syk in neutrophils by antineutrophil cytoplasm antibodies occurs via Fcgamma receptors and CD18. 1497 83

In the present study, we report the activation of murine peritoneal macrophages in vitro on irradiation with sublethal dose of UVB (50 mJ/cm(2)). The activation involves enhanced expression of CD18 molecule and production of nitric oxide (NO), tumor necrosis factor (TNF-alpha) and interleukin-1 (IL-1). Production of NO, TNF-alpha and IL-1 by the macrophages on UVB irradiation was found to peak at 24 h of incubation post UVB irradiation. Increased iNOS, TNF-alpha and IL-1beta mRNAs expression was also observed by reverse transcription and polymerase chain reaction (RT-PCR). The RT-PCR results also showed the increased transcription of IL-6, IL-12, TLR2 and TLR4 genes in UVB-irradiated macrophages. Increased expression of phospho-IkappaB was also observed by immunoblotting in UVB-irradiated macrophages. Investigating the signal transduction pathway responsible for the NO, TNF-alpha and IL-1 production by the UVB-irradiated macrophages, it was observed that the pharmacological inhibitors pertussis toxin, wortmannin, PD98059, SB202190 and genistein blocked NO, TNF-alpha and IL-1 production suggesting the probable involvement of G-proteins, phosphoinositol-3-kinase, p42/44, p38 mitogen activated protein kinases and tyrosine kinases in the above process.
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PMID:In vitro activation of murine peritoneal macrophages by ultraviolet B radiation: upregulation of CD18, production of NO, proinflammatory cytokines and a signal transduction pathway. 1507 50

Bordetella pertussis, the causative agent of whooping cough, secretes among other virulence factors an adenylate cyclase (AC) toxin that is able to enter into eukaryotic cells where it is activated upon binding to endogenous calmodulin (CaM) and synthesizes supraphysiological cAMP levels. In vivo, the AC toxin, through its specific interaction with the CD11b/CD18 integrin, primarily targets phagocytic cells such as neutrophils and macrophages. Because neutrophil priming and activation result in the production of reactive oxygen species that may cause intracellular oxidation, we have examined the biological consequences of the oxidation of CaM methionines upon its interaction with AC. We show here that the interaction of CaM with AC is dependent on the reduced state of methionines, because oxidation of all methionine residues of CaM dramatically decreases its affinity for AC. Peptide methionine sulfoxide reductases A (MsrA) and B (MsrB) were able to partially reduce the oxidized CaM, and these partially "repaired" forms could interact with AC nearly as efficiently as the native protein. We further showed that the CaM.AC complex is resistant to oxidation with tert-butylhydroperoxide, and we identified methionine residues 109, 124, and 145 as critical for binding to AC. The resistance of the AC.CaM complex to oxidation and the ability of AC to be efficiently activated by partially oxidized CaM molecules should allow the toxin to exert its cytotoxic effects on activated neutrophils and contribute to the host colonization.
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PMID:Essential role of methionine residues in calmodulin binding to Bordetella pertussis adenylate cyclase, as probed by selective oxidation and repair by the peptide methionine sulfoxide reductases. 1514 19

Bordetella pertussis secretes an adenylate cyclase toxin (CyaA or ACT) that targets primarily cells expressing the alphaMbeta2 integrin (CD11b/CD18) receptor. This toxin can deliver its N-terminal catalytic AC domain (400 amino acid residues) into the cytosol directly across the cytoplasmic membrane. Various heterologous CD8+, as well as CD4+ T-cell epitopes have been engineered into genetically detoxified CyaA and the resulting toxoids were successfully used as vectors for delivery of inserted epitopes into antigen-presenting cells. Upon processing and presentation, these recombinant CyaAs trigger specific MHC class I and/or class II-restricted T-cell responses both in vitro and in vivo.
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PMID:The adenylate cyclase toxin from Bordetella pertussis--a novel promising vehicle for antigen delivery to dendritic cells. 1514 33

Bordetella pertussis adenylate cyclase (CyaA) is an invasive bacterial toxin that delivers its N-terminal catalytic domain into the cytosol of eukaryotic cells bearing the alpha(M)beta(2) integrin (CD11b/CD18), such as myeloid dendritic cells. This allows use of engineered CyaA for targeted delivery of CD8(+) T cell epitopes into the MHC class I pathway of APC and induction of robust and protective cytotoxic responses. In this study, we demonstrate that CyaA can efficiently codeliver both a CD8(+) T cell epitope (OVA(257-264)) and a CD4(+) T cell epitope (MalE(100-114)) into, respectively, the conventional cytosolic or endocytic routes of processing of murine bone marrow-derived dendritic cells. Upon CyaA delivery, a strong potentiation of the MalE(100-114) CD4(+) T cell epitope presentation is observed as compared with the MalE protein, which depends on CyaA interaction with its CD11b receptor and its subsequent clathrin-mediated endocytosis. In vivo, CyaA induces strong and specific Th1 CD4(+) and CD8(+) T cell responses against, respectively, the MalE(100-114) and OVA(257-264) epitopes. These results underscore the potency of CyaA for design of new vaccines.
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PMID:Antigen targeting to CD11b allows efficient presentation of CD4+ and CD8+ T cell epitopes and in vivo Th1-polarized T cell priming. 1552 45

CD11b-CD18 and other integrins play important roles in immunity and inflammation and require prior activation through inside-out signaling to efficiently bind their ligands. We present evidence for a novel TLR2-dependent signaling pathway that leads to CD11b-CD18 activation in human monocytes or neutrophils upon recognition of Porphyromonas gingivalis fimbriae through CD14. The activated binding-state of CD11b-CD18, which involves induction of conformational changes, was monitored through detection of an activation-specific epitope of CD11b. The ability of fimbriae to induce this activation epitope was significantly inhibited by a mAb to TLR2, but not to TLR4 or unrelated surface molecules. Moreover, the ability of fimbriae to activate CD11b-CD18 was significantly inhibited by pharmacological inhibitors of phosphatidylinositol-3-kinase but not of PKC or of p38 mitogen-activated protein kinase. The signaling pathway activated by fimbriae is distinct from that which is activated by N-formyl-Met-Leu-Phe, a prototypical integrin activator, since the former was insensitive to pertussis toxin. This novel function of TLR2 as a signaling receptor for pathogen-induced activation of CD11b-CD18 may play a significant role in infection-driven chronic inflammatory conditions, such as periodontal disease or atherosclerosis, where P. gingivalis has been implicated.
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PMID:Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll-like receptor 2, and phosphatidylinositol-3-kinase. 1573 63

CR3 (CD11b/CD18) is expressed on neutrophils, and the engagement of CR3 can promote phagocytosis. CR3 serves as the receptor for the Bordetella pertussis adhesin filamentous hemagglutinin (FHA) and for the adenylate cyclase toxin (ACT), which blocks neutrophil function. The influence of CR3, FHA, and ACT on the phagocytosis of B. pertussis by human neutrophils was examined. The surface expression and function of CR3 are regulated. Tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) increased CR3 surface expression, but only TNF-alpha increased the ability of neutrophils to phagocytose B. pertussis, suggesting that elevated CR3 expression alone is not sufficient to promote phagocytosis. Purified FHA and pertussis toxin also increased the surface expression of CR3 on neutrophils, while ACT and the B subunit of pertussis toxin did not affect CR3 expression. FHA-mediated attachment to CR3 can lead to phagocytosis, especially in the absence of ACT. FHA mutants failed to attach and were not phagocytosed by neutrophils. Similarly, an antibody to CR3 blocked both attachment and phagocytosis. The addition of exogenous FHA enhanced the attachment and phagocytosis of wild-type B. pertussis and FHA mutants. Mutants lacking the SphB1 protease, which cleaves FHA and allows the release of FHA from the bacterial surface, were phagocytosed more efficiently than wild-type bacteria. ACT mutants were efficiently phagocytosed, but wild-type B. pertussis or ACT mutants plus exogenous ACT resisted phagocytosis. These studies suggest that the activation and surface expression of CR3, FHA expression, and the efficiency of ACT internalization all influence whether B. pertussis will be phagocytosed and ultimately killed by neutrophils.
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PMID:Influence of CR3 (CD11b/CD18) expression on phagocytosis of Bordetella pertussis by human neutrophils. 1623 29

Nucleotides are important extracellular signaling molecules. It has been established that nucleotides are released from damaged cells, activated platelets and endothelial cells. Thus, at the site of vascular injury, the concentrations of extracellular nucleotides can become elevated. Nucleotides have been shown to cause mobilization of intracellular calcium, upregulation of Mac-1 (CD11b/CD18), degranulation, and chemotaxis in human neutrophils. The goal of this work is to investigate the functional characteristics of nucleotide-receptors in human neutrophils. Nucleotides (ATP and UTP), caused intracellular calcium mobilization in a dose dependent manner. Pharmacological characterization using selective agonists (ATP, UTP), pertussis toxin in human neutrophils and human astrocytoma cells 1321N1 stably expressing P2Y2 or P2Y4 receptors, revealed that human neutrophils express only functional P2Y2 receptors. Treatment of neutrophils with pertussis toxin causes a partial inhibition of nucleotide-induced calcium mobilization. Similarly, by using 1321N astrocytoma cells expressing the P2Y2 receptor we confirmed that calcium mobilization is only partially inhibited by pertussis toxin. The partial resistance of P2Y2-mediated intracellular calcium mobilization suggests that this receptor subtype is coupled not only to a Gi protein, but also to a protein belonging to the Gq-family (most likely G16). In conclusion, we have shown that human neutrophils express functional P2Y2 receptors and all the nucleotide responses are mediated by P2Y2 receptor subtype and that P2Y2 receptors are the functional able to trigger intracellular signaling event in human neutrophils through dual activation of different G proteins.
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PMID:[Functional characteristics of nucleotide-receptors in human neutrophils]. 1660 54


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