Die Bedeutung des Koagulationsfaktors XIII in der angeborenen Immunantwort gegen Streptokokken-Infektionen

Although coagulation is an essential process of hemostasis and wound healing several studies delineate an additional role of the intrinsic coagulation pathway, also known as “contact system”, in the early immune defense against bacterial infections. Thus, contact system activation on the surface of bacteria such as Streptococcus pyogenes (S. pyogenes) leads to the induction of the entire clotting cascade resulting in pathogen immobilization within the generated fibrin network. As coagulation factor XIII (FXIII) was identified as a key factor within this process, the objective of this study was the further investigation of the importance of FXIII during streptococcal infections. Results obtained from in vitro clotting assays indicated that FXIII selectively influenced the entrapment of S. pyogenes bacteria of the serotype M1. The relevance of this FXIII-mediated entrapment for the host defense against S. pyogenes M1 was investigated in vivo using a murine model of streptococcal skin and soft tissue infection. Mice deficient in FXIII expression developed a more severe infection and systemic complications after inoculation with S. pyogenes M1 than wild type animals as demonstrated by prolonged clotting times, elevated the Interleukin-6 levels, increased bacterial dissemination and decreased survival. These results illustrated a protective role of FXIII during S. pyogenes M1 infection. Furthermore, local reconstitution of FXIII-deficient mice with a human FXIII-concentrate (Fibrogammin®P) after S. pyogenes inoculation resulted in reduced systemic complications and an improved survival of infected FXIII-deficient mice. Furthermore, the capacity of the S. pyogenes M1 protein to inhibit the fibrinogen conversion during in vitro clotting, a mechanism that could help S. pyogenes M1 bacteria to counteract their entrapment within fibrin clots, was observed. Moreover, the A region of the M1 protein was required for the inhibition of the fibrinogen conversion. However, it could be demonstrated that FXIII counteracted the M1 protein-mediated inhibition of fibrinogen conversion and supported the entrapment of S. pyogenes within the fibrin network. In the absence of FXIII, the lack of bacterial immobilization may explain the more extensive bacterial dissemination and infection severity observed in FXIII-deficient mice after inoculation with S. pyogenes M1.Die Blutgerinnung bzw. Koagulation ist ein essentieller Prozess der Hämostase und Wundheilung. Vorangegangene Studien beschrieben jedoch eine weitere Bedeutung des intrinsischen Weges der Koagulation – auch als Kontaktsystem bezeichnet - in der frühen Abwehr bakterieller Infektionen. Kontaktaktivierung auf der Oberfläche von Bakterien wie Streptococcus pyogenes, (S. pyogenes) induziert die gesamte Gerinnungskaskade und vermittelt die Immobilisierung der eindringenden Bakterien in Fibrinnetzwerke. Der Koagulationsfaktor XIII (FXIII) wurde als Schlüsselkomponente dieses Prozesses identifiziert. Im Rahmen dieser Arbeit wurde deshalb die Bedeutung von FXIII während Streptokokken-infektionen untersucht. Die Ergebnisse der in vitro Gerinnungsexperimente deuten darauf, dass FXIII ausschließlich den Einschluss von S. pyogenes-Bakterien des Serotyps M1 in Fibringerinnsel beeinflusst. Die Bedeutung der FXIII-vermittelten Immobilisierung in der Immunabwehr des Wirtes gegen S. pyogenes M1 in vivo wurde mit Hilfe eines Mausmodells für S. pyogenes M1-induzierte Haut- und Gewebeinfektionen untersucht. Dabei entwickelten Mäuse, denen FXIII fehlte, schwerwiegendere, systemische Komplikationen nach der Infektion mit S. pyogenes M1 im Vergleich zu Wildtyp-Mäusen. Dies wurde durch die Verlängerung der Gerinnungszeiten, den erhöhten Interleukin 6-Spiegel, der erhöhten Verbreitung der Bakterien sowie das verminderte Überleben dieser Mäuse belegt. Weiterhin wurden FXIII-defiziente Mäuse nach der Infektion mit einem humanen FXIII-Konzentrat (Fibrogammin®P) rekonstituiert, wodurch systemische Komplikationen vermindert und das Überleben dieser Mäuse erhöht wurde. Weiterhin wurde gezeigt, dass das M1-Protein von S. pyogenes den Fibrinogenumsatz in vitro inhibiert und dadurch dem Einschluss der Bakterien am Infektionsort entgegenwirken kann. Die A-Region des M1-Proteins wurde dabei als die Proteinregion identifiziert, welche für die Inhibierung verantwortlich ist. Dennoch wurde nachgewiesen, dass FXIII der M1-Protein-vermittelten Inhibierung des Fibrinogenumsatzes entgegenwirkt und den Einschluss der Bakterien unterstützt. Der fehlende Einschluss der Bakterien in der Abwesenheit von FXIII, könnte demnach die stärkere Verbreitung von S. pyogenes im Wirt und den schwereren Verlauf von S. pyogenes M1-vermittelten Infektionen in FXIII-defizienten Mäusen erklären

The role of coagulation/fibrinolysis during Streptococcus pyogenes infection.

The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis and is a host defense mechanism that protects the integrity of the vascular system after tissue injury. During bacterial infections, the coagulation system cooperates with the inflammatory system to eliminate the invading pathogens. However, pathogenic bacteria have frequently evolved mechanisms to exploit the hemostatic system components for their own benefit. Streptococcus pyogenes, also known as Group A Streptococcus, provides a remarkable example of the extraordinary capacity of pathogens to exploit the host hemostatic system to support microbial survival and dissemination. The coagulation cascade comprises the contact system (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway), both leading to fibrin formation. During the early phase of S. pyogenes infection, the activation of the contact system eventually leads to bacterial entrapment within a fibrin clot, where S. pyogenes is immobilized and killed. However, entrapped S. pyogenes can circumvent the antimicrobial effect of the clot by sequestering host plasminogen on the bacterial cell surface that, after conversion into its active proteolytic form, plasmin, degrades the fibrin network and facilitates the liberation of S. pyogenes from the clot. Furthermore, the surface-localized fibrinolytic activity also cleaves a variety of extracellular matrix proteins, thereby enabling S. pyogenes to migrate across barriers and disseminate within the host. This review summarizes the knowledge gained during the last two decades on the role of coagulation/fibrinolysis in host defense against S. pyogenes as well as the strategies developed by this pathogen to evade and exploit these host mechanisms for its own benefit

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helmholtz-hzi.de The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis and is a host defense mechanism that protects the integrity of the vascular system after tissue injury. During bacterial infections, the coagulation system cooperates with the inflammatory system to eliminate the invading pathogens. However, pathogenic bacteria have frequently evolved mechanisms to exploit the hemostatic system components for their own benefit. Streptococcus pyogenes, also known as Group A Streptococcus, provides a remarkable example of the extraordinary capacity of pathogens to exploit the host hemostatic system to support microbial survival and dissemination. The coagulation cascade comprises the contact system (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway), both leading to fibrin formation. During the early phase of S. pyogenes infection, the activation of the contact system eventually leads to bacterial entrapment within a fibrin clot, where S. pyogenes is immobilized and killed. However, entrapped S. pyogenes can circumvent the antimicrobial effect of the clot by sequestering host plasminogen on the bacteria