| 1. |
- Bengtson, Sara, et al.
(författare)
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Activation of TAFI on the Surface of Streptococcus pyogenes Evokes Inflammatory Reactions by Modulating the Kallikrein/Kinin System
- 2009
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 1:1, s. 18-28
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Tidskriftsartikel (refereegranskat)abstract
- Bacteria-controlled regulation of host responses to infection is an important virulence mechanism that has been demonstrated to contribute to disease progression. Here we report that the human pathogen Streptococcus pyogenes employs the procarboxypeptidase TAR (thrombin-activatablefibrinolysis inhibitor) to modulate the kallikrein/kinin system. To this end, bacteria initiate a chain of events starting with the recruitment and activation of TAFI. This is followed by the assembly and induction of the contact system at the streptococcal surface, eventually triggering the release of bradykinin (BK). BK is then carboxyterminally truncated by activated TAFI, which converts the peptide from a kinin B-2 receptor ligand to a kinin B-1 receptor (B1R) agonist. Finally, we show that streptococcal supernatants indirectly amplify the B1R response as they act on peripheral blood mononuclear cells to secrete inflammatory cytokines that in turn stimulate upregulation of the B1R on human fibroblasts. Taken together our findings implicate a critical and novel role for streptococci-bound TAR, as it processes BK to a B1R agonist at the bacterial surface and thereby may redirect inflammation from a transient to a chronic state. Copyright (C) 2008 S. Karger AG, Basel
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| 2. |
- Malmström, Erik, et al.
(författare)
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Protein C inhibitor - a novel antimicrobial agent
- 2009
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 5:12, s. e1000698-
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Tidskriftsartikel (refereegranskat)abstract
- Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequently leads to their permeabilization. As shown by negative staining electron microscopy, treatment of Escherichia coli or Streptococcus pyogenes bacteria with PCI triggers membrane disruption followed by the efflux of bacterial cytosolic contents and bacterial killing. The antimicrobial activity of PCI is located to the heparin-binding site of the protein and a peptide spanning this region was found to mimic the antimicrobial activity of PCI, without causing lysis or membrane destruction of eukaryotic cells. Finally, we show that platelets can assemble PCI on their surface upon activation. As platelets are recruited to the site of a bacterial infection, these results may explain our finding that PCI levels are increased in tissue biopsies from patients suffering from necrotizing fasciitis caused by S. pyogenes. Taken together, our data describe a new function for PCI in innate immunity.
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| 3. |
- Verkleij, Chantal J. N., et al.
(författare)
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The effects of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor
- 2009
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 102:3, s. 460-468
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies have shown a strong association between type 2 diabetes mellitus and cardiovascular diseases, and hypofibrinolysis may contribute to this phenomenon. The aim of this study was to determine the effect of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor (TAR). Hyperglycaemia was mimicked in vitro by incubation of TAFI with glyceraldehyde and in vivo by hyperglycaemic clamping of healthy volunteers. The effects of long-term hyperglycaemia in vivo on TAR were investigated by comparing TAFI from poorly regulated and tightly regulated patients with type 2 diabetes. In vitro glycated TAR showed an altered migration pattern on SDS-PAGE due to aggregation. Glycated TAFI showed decreased activity after activation by thrombin-thrombomodulin in a glyceraldehyde-dose-dependent manner and a reduced anti-fibrinolytic potential. In vivo, no differences in TAR parameters were found after hyperglycaemic clamping of healthy volunteers and between tightly and poorly regulated patients with type 2 diabetes. Moreover, TAR purified from poorly regulated and tightly regulated patients with type 2 diabetes migrated similarly on SDS-PAGE, indicating little or no glycation of the protein. Despite the deleterious effects of glycation of TAR in vitro on its function,TAFI was neither affected by hyperglycaemic clamping, nor by long-term hyperglycaemia in patients with type 2 diabetes. This is in contrast to fibrinolytic factors as plasminogen-activator inhibitor I and tissue-type plasminogen activator, which are affected. We therefore hypothesise that a normally functioning TAR under hyperglycaemic conditions may tip the haemostatic balance towards hypofibrinolysis, which may contribute to the development of cardiovascular diseases in type 2 diabetic patients.
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