Contact system activation in severe infectious diseases

Abstract

Hemostasis is a sensitive and tightly regulated process, involving vascular endothelium and blood cells, as well as factors of the coagulation and fibrinolytic cascades. In severe and invasive infectious diseases, the equilibrium between the procoagulant and anticoagulant status of the host may change dramatically and can induce life-threatening complications. A growing body of evidence suggests that the contact system, also known as the intrinsic pathway of coagulation or kallikrein/kinin system, participate in these processes. Contact activation leads to the release of the highly potent proinflammatory peptide bradykinin and initiates the intrinsic pathway of coagulation. Several studies have shown a systemic activation of the contact system in animal models of severe bacterial infections, and similar findings were also reported when monitoring patients suffering from sepsis, severe sepsis, or septic shock. Complications resulting from a systemic activation of the contact system are pathologically high levels of bradykinin, consumption of contact factors, and a subsequent induction of inflammatory reactions. These conditions may contribute to serious complications such as hypotension and vascular leakage. Here, we summarize the state of the art in this field of research with a focus on the contact system, and we also discuss a potential role for the contact system as a target for the development of novel antimicrobial strategies.

Extracellular aspartic protease SAP2 of Candida albicans yeast cleaves human kininogens and releases proinflammatory peptides, Met-Lys-bradykinin and des-Arg9-Met-Lys-bradykinin

“…Involved in almost any kind of infl ammation, the kinins induce a secondary release of pro-infl ammatory mediators such as nitric oxide, prostaglandins and cytokines by a variety of effector cells (Blais et al , 2000 ;Moreau et al , 2005 ). The activation of the kininforming system has been suggested to constitute an important part of the human host defense against microbial infections (Oehmcke and Herwald , 2010 ). However, some kinin-exerted effects can be considered as ' benefi cial ' to pathogens, such as the enhancement of vascular permeability, which causes the infl ow of plasma and facilitates the availability of nutrients and the spreading the pathogen within the host organism (Potempa and Pike , 2009 ).…”

A cofactor for factor XI activation

“…The KKS participates in a number of homeostatic and host-defense functions, including the innate immune response to invading microorganisms. 4,5 KKS components assemble and are activated on the surface of microorganisms, generating antimicrobial peptides and contributing to complement activation. 5 The capacity of the KKS to bind to surfaces is also important for initiating blood coagulation in vitro in the activated partial thromboplastin time assay (aPTT) used in clinical practice.…”

“…4,5 KKS components assemble and are activated on the surface of microorganisms, generating antimicrobial peptides and contributing to complement activation. 5 The capacity of the KKS to bind to surfaces is also important for initiating blood coagulation in vitro in the activated partial thromboplastin time assay (aPTT) used in clinical practice. In the aPTT, anionic substances such as purified earths trigger reciprocal activation of factor XII and prekallikrein in a process called contact activation.…”

“…4 A more recent study of murine T-cell clones specific for an MHC-class II alloantigen showed mixed results: 3 clones responded to 2 or 3 different peptides inserted into the groove between the ␣-helices, whereas 6 clones appeared to be specific for a single peptide. 5 Amir et al isolated 56 T-cells clones from a patient with GVHD after hematopoietic cell transplantation from a related donor. 1 The related donor and recipient were HLA genotypically identical except at HLA-A.…”

Accentuate the (Gram) positive

“…Heiko Herwald at Lund University has been studying activation of the kallikein/kinin or contact system by S. aureus and GAS toxins and its role in the severe manifestations of sepsis such as hypotension and vascular leakage. From these data, it is suggested that blockage of kinin receptors or administration of C1 inhibitor, itself a regulator of the contact system, could have beneficial effects on mortality and lung injury induced by Gram-positive bacterial infection [12]. Profound alterations in the microcirculation, a byproduct of localized leukocyte adhesion and activation coupled to the systemic inflammatory response, are also manifested in Grampositive bacterial sepsis.…”