The role of coagulation factor XIII in the early innate immune response against streptococcal infections

Abstract

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.