Staphylococcus aureus Induces Release of Bradykinin in Human Plasma

Abstract

Staphylococcus aureus is a prominent human pathogen. Here we report that intact S. aureus bacteria activate the contact system in human plasma in vitro, resulting in a massive release of the potent proinflammatory and vasoactive peptide bradykinin. In contrast, no such effect was recorded with Streptococcus pneumoniae. In the activation of the contact system, blood coagulation factor XII and plasma kallikrein play central roles, and a specific inhibitor of these serine proteinases inhibited the release of bradykinin by S. aureus in human plasma. Furthermore, fragments of the cofactor H-kininogen of the contact system efficiently blocked bradykinin release. The results suggest that activation of the contact system at the surface of S. aureus and the subsequent release of bradykinin could contribute to the hypovolemic hypotension seen in patients with severe S. aureus sepsis. The data also suggest that the contact system could be used as a target in the treatment of S. aureus infections.Gram-positive bacteria are currently as common as gramnegative bacteria in causing sepsis, and Staphylococcus aureus and Streptococcus pneumoniae are the most frequently isolated pathogens in gram-positive sepsis (5, 6, 16). These species can give rise to septic shock, a condition with a high mortality rate despite antibiotic treatment and improvements in intensive care. The pathogenesis of sepsis is not fully understood. However, there appears to be a common pathway by which both gram-negative and gram-positive bacteria induce the production of different inflammatory mediators, such as factors of the complement, coagulation, and contact systems, which act together with cytokines to form a complex inflammatory network (5, 9).The contact system consists of three enzymatic factors, factor XI (FXI), FXII, and plasma prekallikrein (PK), and the nonenzymatic cofactor H-kininogen (HK) (24). Activation of FXII is the initial step leading to the formation of kallikrein and activated FXI. As a result, bradykinin (BK), a nonapeptide, is released from HK. BK induces vasodilatation and increased microvascular permeability, effects that in part are mediated by the secondary release of other mediators (for instance, nitric oxide and platelet activating factor) via activation of BK receptors of the vascular endothelium. The contact system can also be activated directly by endotoxin and microbial proteinases (11,15,18).When injected into animals, BK reduces peripheral vascular resistance, leading to hypotension and elevated cardiac output (26), and several animal studies have shown that activation of the contact system correlates with irreversible hypotension during sepsis (25,26). Investigations of humans have revealed that factors of the contact system are consumed in plasma of patients with severe sepsis and, especially, that persistently low levels of FXII are a bad prognostic sign (14,21,27,28). A pathogenic role for the contact system is also suggested by observations that it can be activated by Streptococcus pyogenes, Salmonella, and Escher...

Staphylococcus aureus-induced clotting of plasma is an immune evasion mechanism for persistence within the fibrin network

“…1(a) shows that already after 30 min, increased activity of the coagulation factor was seen at the surface of all three strains when incubated with normal, but not with plasma prekallikrein-deficient plasma. These findings suggested that the thrombin activity measured was caused by an activation of the contact system which occurred within minutes upon incubation of S. aureus with human plasma (Mattsson et al, 2001). Longer incubation of coagulase-deficient bacteria in normal human plasma did not promote further cleavage of the substrate, whereas a significant increase was noted when WT strains SH1000 or 8325-4 WT were used (Fig.…”

The Conversion of Fibrinogen to Fibrin at the Surface of Curliated Escherichia coli Bacteria Leads to the Generation of Proinflammatory Fibrinopeptides

“…36). However, coagulation disorders during bacterial infection can also be induced locally, as exemplified by the ability of some bacterial species, such as E. coli, Salmonella, Staphylococcus aureus, and Streptococcus pyogenes, to assemble and activate the contact system (also known as the kallikrein/kinin system or intrinsic pathway of coagulation) at their surface (12,15,(37)(38)(39). This mechanism leads to a hypocoagulative state as well as to the generation of proinflammatory kinins.…”

Immunological Mechanisms Underlying the Genetic Predisposition to Severe Staphylococcus aureus Infection in the Mouse Model

“…Because bradykinin is one of the most potent endogenous vasoactive peptides 37 and previous studies have shown that S. aureus can induce the release of bradykinin by activating the contact system, also known as the intrinsic pathway of coagulation, 38 we hypothesized that activation of the contact system in the A/J and the concomitant release of bradykinin may play an impor- tant role in the induction of the observed vascular leakage. To test this hypothesis, we determined the extent of contact activation in S. aureus-infected A/J and C57BL/6 mice by measuring the activated partial thromboplastin time (aPTT).…”