Contact activation on bacterial surfaces - a virulence mechanism
Sammanfattning: Life-threatening conditions from bacterial infections are a major clinical problem. During a severe infection, the host responds by a massive release of pro-inflammatory mediators together with a systemic activation of systems such as the coagulation, fibrinolytic, and complement systems. These events could result in the development of complications such as disseminated intravascular coagulation and shock. This thesis is focused on the molecular interactions between the human coagulation system, in particular the contact system, and bacteria such as Escherichia coli and Salmonella typhimurium expressing the surface organelle curli, and Staphylococcus aureus. Curli expressing E. coli and Salmonella bacteria were found capable of activating the contact system resulting in the release of the potent pro-inflammatory mediator bradykinin. An in vivo infectious model showed that blocking of contact system activation on the bacterial surface prevented tissue damage, coagulation dysfunctions and inflammatory reactions. Moreover, also S. aureus bacteria were able to trigger an activation of the contact system on their surface leading to the release of bradykinin. The curli organelle of E. coli has an unusually broad binding specificity of a number of human plasma and extracellular matrix proteins. The protein binding sites of the curli subunit csgA were mapped to two regions in the COOH- or the NH2-terminal part of csgA. Activation of the contact system on curliated E. coli bacteria was also found to trigger an activation of the coagulation cascade on the bacterial cell surface. Blocking of contact system activation also inhibited the induction of the coagulation cascade. Furthermore, this inhibition prevented generation of fibrinopeptides that in vivo induced the production of pro-inflammatory cytokines. These investigations indicate an important role for the coagulation and contact systems during severe infections.
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