Treatment of invasive streptococcal infection with a peptide derived from human high-molecular weight kininogen

Oehmcke, Sonja; Shannon, Oonagh; Köckritz-Blickwede, Maren von; Mörgelin, Matthias; Linder, Adam; Olin, Anders I.; Björck, Lars; Herwald, Heiko

doi:10.1182/blood-2008-10-182527

Cited by 42 publications

(46 citation statements)

References 40 publications

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“…The contact system is a link between inflammation and coagulation, and contact activation has been demonstrated at the surface of several species of pathogenic bacteria and fungi, such as Candida (1,2,14,16,20). Inhibition of this system blocks plasma leakage and improves the outcome in animal models of invasive bacterial infection (25,27).…”

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confidence: 99%

Activation of the Contact System at the Surface of Fusobacterium necrophorum Represents a Possible Virulence Mechanism in Lemièrre's Syndrome

et al. 2011

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Fusobacterium necrophorum causes Lemièrre's syndrome, a serious disease with septic thrombophlebitis of the internal jugular vein, pulmonary involvement, and systemic inflammation. The contact system is a link between inflammation and coagulation, and contact activation by the bacteria could therefore contribute to the abnormal coagulation and inflammation seen in patients with Lemièrre's syndrome. In this study, F. necrophorum was found to bind radiolabeled high-molecular-weight kininogen (HK), a central component of the contact system. Binding was inhibited by the addition of unlabeled HK and domain D5 of HK but not other components of the contact system, indicating a specific interaction mediated through the D5 region. Binding of HK was significantly reduced after pretreatment of the bacteria with trypsin, suggesting that surface proteins are involved in HK binding. Incubation of the bacteria with human plasma resulted in an HK breakdown pattern suggestive of bradykinin release, and bradykinin was also detected in the supernatant. In addition, we show that factor XI (FXI), another component of the contact system, binds to F. necrophorum and that the bound FXI reconstitutes the activated partial thromboplastin time of FXI-deficient plasma. Thrombin activity was detected at the surface of the bacteria following incubation with plasma, indicating that the intrinsic pathway of coagulation is activated at the surface. This activity was completely blocked by inhibitors of the contact system. The combined results show that the contact system is activated at the surface of F. necrophorum, suggesting a pathogenic role for this system in Lemièrre's syndrome.

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Activation of the Contact System at the Surface of Fusobacterium necrophorum Represents a Possible Virulence Mechanism in Lemièrre's Syndrome

et al. 2011

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“…The S. pyogenes M1 strain has previously been shown to bind and activate contact factors on its surface (24,25). To test whether S. pyogenes M49 and M1 strains trigger contact activation on their surfaces, the bacteria were incubated with human plasma.…”

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confidence: 99%

Streptococcus pyogenes Triggers Activation of the Human Contact System by Streptokinase

et al. 2015

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Severe invasive infectious diseases remain a major and life-threatening health problem. In serious cases, a systemic activation of the coagulation cascade is a critical complication that is associated with high mortality rates. We report here that streptokinase, a group A streptococcal plasminogen activator, triggers the activation of the human contact system. Activation of contact system factors at the surface of the Streptococcus pyogenes serotype M49 is dependent on streptokinase and plasminogen. Our results also show that secreted streptokinase is an efficient contact system activator, independent from a contact surface. This results in the processing of high-molecular-weight kininogen and the release of bradykinin, a potent vascular mediator. We further investigated whether the ability of 50 different clinical S. pyogenes isolates to activate the contact system is associated with an invasive phenotype. The data reveal that isolates from invasive infections trigger an activation of the contact system more potently than strains isolated from noninvasive infections. The present study gives new insights into the mechanisms by which S. pyogenes triggers the human contact system and stresses the function of soluble and surface located plasmin exploited as a group A streptococcal virulence factor through the action of streptokinase.

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“…Further investigations are needed to address this potential interaction. However, this property of HKH20 could be useful in treating BK-induced inflammatory (48) response and treating bacterial infections (49,50). Nonetheless, HK interaction with B 2 is strong enough to trigger the B 2 receptor signaling cascade.…”

Section: Discussionmentioning

confidence: 99%

High Molecular Weight Kininogen Activates B2 Receptor Signaling Pathway in Human Vascular Endothelial Cells

Kolte

Osman

Yang

et al. 2011

Journal of Biological Chemistry

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The nonenzymatic cofactor high molecular weight kininogen (HK) is a precursor of bradykinin (BK). The production of BK from HK by plasma kallikrein has been implicated in the pathogenesis of inflammation and vascular injury. However, the functional role of HK in the absence of prekallikrein (PK), the proenzyme of plasma kallikrein, on vascular endothelial cells is not fully defined. In addition, no clinical abnormality is seen in PKdeficient patients. Therefore, an investigation into the effect of HK, in the absence of PK, on human pulmonary artery endothe- The plasma kallikrein-kinin system (KKS) 2 consists of three proenzymes; factor XII (FXII, Hageman factor), prekallikrein (PK, Fletcher factor), and factor XI (FXI, plasma thromboplastin antecedent) as well as one cofactor; high molecular weight kininogen (HK, Fitzgerald factor). KKS is involved in the regulation of hemodynamics, inflammation, complement activation, angiogenesis, thrombosis, and fibrinolysis. Basically, all these proposed roles represent a range of overlapping effects that contribute to various extents toward vasodilation and healing. Therefore, the plasma KKS can be considered to have a spectrum of physiological effects, ranging at one extreme from a hemostatic state of vasodilation and promotion of smooth blood flow, all the way to a prothrombotic state. It is conceivable to suggest that other mechanisms proposed about respiratory, retinal, and renal systems can fit into this spectrum of physiological effects (1-3). There is accumulating evidence suggesting that when the plasma KKS is activated, the results are a sequential release of proteolytic enzymes and vasoactive peptides, generation of both angiogenic and anti-angiogenic molecules, stabilization of thrombus, and an increase in protease inhibitor activity in blood (4 -7). The activation of HK-PK complex on endothelial cells triggers vasodilation through smooth muscle relaxation, inhibits platelet aggregation, and induces proinflammatory responses. Of note, the direct assembly of HK, PK, and FXII on vascular smooth muscle cells (VSMC) also results in the activation of PK to kallikrein (8). The induction of these physiological reactions is caused by the release of the vasoactive peptide bradykinin (BK) from HK by kallikrein. Bradykinin B 2 receptor activation by BK mediates the activation of endothelial nitric-oxide synthase (eNOS) and phospholipase A 2 (PLA 2 ) leading to production of nitric oxide (NO) and prostacylin (PGI 2 ). Evidence suggests that BK phosphorylates p44/42 mitogen-activated protein kinase in VMSC, which is blocked by BK antagonist HOE-140 (8).Besides having a direct effect on blood vessels, the HK-PK complex has also been shown to mediate the effects of other pro-inflammatory molecules. Recent study suggests that the inhibitors of both BK and factor XII activity protect from mast cell-induced effects not only in patients but also in genetically engineered mouse models. The authors proposed that this class of inhibitors could be useful to treat allergic diseases (9)....

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Treatment of invasive streptococcal infection with a peptide derived from human high-molecular weight kininogen

Cited by 42 publications

References 40 publications

Activation of the Contact System at the Surface of Fusobacterium necrophorum Represents a Possible Virulence Mechanism in Lemièrre's Syndrome

Activation of the Contact System at the Surface of Fusobacterium necrophorum Represents a Possible Virulence Mechanism in Lemièrre's Syndrome

Streptococcus pyogenes Triggers Activation of the Human Contact System by Streptokinase

High Molecular Weight Kininogen Activates B2 Receptor Signaling Pathway in Human Vascular Endothelial Cells

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