2015
DOI: 10.1038/icb.2015.87
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Pore‐formation by adenylate cyclase toxoid activates dendritic cells to prime CD8+ and CD4+ T cells

Abstract: The adenylate cyclase toxin-hemolysin (CyaA) of Bordetella pertussis is a bi-functional leukotoxin. It penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into their cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, ~1300 residue-long RTX hemolysin moiety of CyaA forms cation-selective pores and permeabilizes target cell membrane for efflux of cytosolic potassium ions. The non-enzymatic CyaA-AC(-) toxoid, has repeatedly been successfully exploited … Show more

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Cited by 20 publications
(23 citation statements)
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References 65 publications
(135 reference statements)
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“…In the second line, the cAMP-mediated downregulation of pro-inflammatory IL-12 and TNF-α production and the upregulation of anti-inflammatory IL-10 cytokine release by myeloid cells, would skew the adaptive immune responses to infection and protract bacterial colonization. In contrast, the pore-forming activity of CyaA was shown to elicit potassium efflux and thereby contributes activation of the p38 and JNK kinases in toxin-permeabilized monocyte-derived cells59. This then synergizes with TLR-mediated signaling of bacterial components towards promoting NALP3 inflammasome assembly and induction of pro-inflammatory IL-1β cytokine release13.…”
Section: Discussionmentioning
confidence: 99%
“…In the second line, the cAMP-mediated downregulation of pro-inflammatory IL-12 and TNF-α production and the upregulation of anti-inflammatory IL-10 cytokine release by myeloid cells, would skew the adaptive immune responses to infection and protract bacterial colonization. In contrast, the pore-forming activity of CyaA was shown to elicit potassium efflux and thereby contributes activation of the p38 and JNK kinases in toxin-permeabilized monocyte-derived cells59. This then synergizes with TLR-mediated signaling of bacterial components towards promoting NALP3 inflammasome assembly and induction of pro-inflammatory IL-1β cytokine release13.…”
Section: Discussionmentioning
confidence: 99%
“…3B). Such synergy would have been expected to result from the impact of toxin-provoked Ca 2+ influx on PKC activity and from perturbation of ion homeostasis upon cell permeabilization by the inserted CyaA pores, which activates MAPK signaling (46)(47)(48). The impact of cAMP signaling thus overrode the impact of the poreforming activity.…”
Section: Discussionmentioning
confidence: 99%
“…In parallel, the Hly forms small cation-selective pores that permeabilize the cytoplasmic membrane of target cells and account for the moderate hemolytic activity of CyaA on erythrocytes (25,26). Cell permeabilization by Hly also elicits efflux of cytosolic K ϩ ions and activates the p38 and Jun N-terminal protein kinase (JNK) kinases (27), thus contributing to Toll-like receptor (TLR)-induced NALP3 inflammasome formation and interleukin-1␤ (IL-1␤) secretion by dendritic cells (DCs) (28). The pore-forming activity of CyaA further synergizes with cAMP signaling elicited by the AC enzyme in bringing about the overall cytotoxic (cytolytic) potency of CyaA (29,30).…”
mentioning
confidence: 99%