Contact activation in shock caused by invasive group A Streptococcus pyogenes

Sriskandan, Shiranee; Kemball-Cook, Geoff; Moyes, David L.; Canvin, James R.; Tuddenham, E G D; Cohen, Jonathan

doi:10.1097/00003246-200011000-00025

Cited by 38 publications

(28 citation statements)

References 26 publications

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“…Mice showed systemic signs of sickness 8 to 12 hours after infection. To measure clotting times, 8 groups of female BALB/c mice were infected; and after various time points (0,4,6,10,12,18,24, and 42 hours), the animals were anesthetized with isofluorane and terminal blood samples were taken. Approximately 0.5 mL of blood was drawn by cardiac puncture into polypropylene tubes containing one-tenth volume of 3.8% trisodium citrate.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…Contact activation in vivo and treatment with HKH20. Mice were injected subcutaneously in the neck with 2 ϫ 10 7 CFU S pyogenes bacteria, plasma was collected at 0, 4,6,10,12,18,24, and 42 hours after infection (n ϭ 2-6/group), and aPTT (A) and PT (B) were measured immediately. *P Ͻ .05; ***P Ͻ .001.…”

Section: The Effect Of Hkh20 Treatment On Survivalmentioning

confidence: 99%

“…8 Several reports have described contact system activation in various animal models of infection with different pathogens. [9][10][11][12][13] Contact activation has been seen in all animal species tested, including baboons and rats 9,11 and also in mice, where the degree of activation varies between mouse strains. 13 Thus, animal models of infection may be useful tools to study contact system inhibition for therapeutic purposes.…”

Section: Introductionmentioning

confidence: 99%

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

Oehmcke

Shannon

Köckritz-Blickwede

et al. 2009

Blood

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Sepsis and septic shock remain an important medical problem, emphasizing the need to identify novel therapeutic opportunities. Hypovolemic hypotension, coagulation dysfunction, disturbed microcirculation, and multiorgan failure resulting from vascular leakage are often observed in these severe conditions. In the present study, we find that HKH20, a peptide derived from human high-molecularweight kininogen (HK), down-regulates inflammatory reactions caused by Streptococcus pyogenes in a mouse model of sepsis. HK is a component of the proinflammatory and procoagulant contact system. Activation of the contact system in the bloodstream by S pyogenes leads to massive tissue damage in the lungs of the infected mice, which eventually results in the death of the animals. HKH20 inhibits activation of the contact system and protects mice with invasive S pyogenes infection from lung damage. In combination with clindamycin treatment, the peptide also significantly prolongs the survival of infected mice. IntroductionSepsis and septic shock are complications of bacterial infections that are, despite treatment with antibiotics and improved intensive care, associated with high mortality rates. Streptococcus pyogenes is a major human pathogen that mainly causes skin and throat infections. These infections are normally superficial and selflimiting, but they occasionally develop into the serious and life-threatening conditions streptococcal toxic shock syndrome and necrotizing fasciitis. 1 The molecular mechanisms behind the pathogenesis of these critical conditions are still not fully understood. However, a growing body of evidence suggests that they are the result of an uncontrolled host inflammatory response induced by the pathogen. A systemic activation of proteolytic host cascades, such as the complement, coagulation, and contact systems, plays an important role, together with a massive release of proinflammatory cytokines. 2 Previous work has shown that S pyogenes is able to assemble and activate the human contact system on its surface. 3 The contact system, also known as the intrinsic pathway of coagulation or the kallikrein-kinin system, is involved in normal hemostasis and inflammation. [4][5][6] It is composed of 4 components: factor XI (FXI), FXII, plasma kallikrein (PK), and high-molecular-weight kininogen (HK). Under physiologic conditions, these factors circulate in their inactive forms in the bloodstream or are bound to the surface of different cell types, such as endothelial cells, platelets, and polymorphonuclear neutrophils (PMNs). On activation, the contact system triggers the intrinsic pathway of coagulation via activation of FXI by FXII and evokes the release of bradykinin (BK) from the HK precursor by the action of PK. BK, a peptide consisting of 9 amino acids, is a potent proinflammatory mediator. Thus, BK has been shown to evoke the generation of nitric oxide and other inflammatory substances (eg, prostaglandins and leukotrienes), reduce blood pressure, and induce fever. Notably, and probably more importan...

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Section: Animal Experimentsmentioning

confidence: 99%

Section: The Effect Of Hkh20 Treatment On Survivalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Oehmcke

Shannon

Köckritz-Blickwede

et al. 2009

Blood

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“…However, various reports of decreasing profit in dairy farming have been identified where improvements can be made (Bishop, 1964). Of them, postpartum uterine infection is the majorcause of economic loss in dairy cows (Fox et al, 2002;Sriskandan et al, 2000). It may be due to a longer calving interval, costs of extra services, treatment and increased culling rate (Drillich et al, 2005;Gilbert et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Bacterial Pathogens and Antibiotic Susceptibility Patterns of Cervico-Vaginal Discharges in Cross Bred Repeat Breeding Heifer Cows

Ahuja¹,

Cheema²,

Narang³

et al. 2017

Int.J.Curr.Microbiol.App.Sci

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“…In addition, the surface-bound M protein, one of the classical virulence determinants of GAS, has been demonstrated to bind HK, followed by bradykinin generation (9,10). Binding and assembly of contact system factors on the bacterial surface are thought to be sufficient to activate this proteolytic system (6); however, additional mechanisms must exist, since Sriskandan et al documented that streptococcal culture supernatants were able to activate PK in vitro (11). Many pathogenic streptococci secrete streptokinase in order to accelerate the conversion of human plasminogen to plasmin (12).…”

mentioning

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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Contact activation in shock caused by invasive group A Streptococcus pyogenes

Abstract: Prolongation of activated partial thromboplastin time in streptococcal toxic shock syndrome is associated with activation of the contact system, possibly contributing to the profound shock associated with streptococcal toxic shock syndrome.

Cited by 38 publications

References 26 publications

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

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

Bacterial Pathogens and Antibiotic Susceptibility Patterns of Cervico-Vaginal Discharges in Cross Bred Repeat Breeding Heifer Cows

Streptococcus pyogenes Triggers Activation of the Human Contact System by Streptokinase

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