The role of human factor XIII in infectious diseases
Final Report Abstract
The general aim of this project was the identification of a novel function for coagulation factor XIII (fXIII) in the innate immune defense against invading bacterial pathogens. The intrinsic pathway of coagulation also known as the contact system is activated on the surface of bacterial pathogens, such as E. coli, S. aureus and S. pyogenes when they were incubated together with human plasma, which finally leads to fXIII-activation. Our results show that bacteria are entrapped within the clot in an fXIII-dependent manner. Surface proteins of bacterial pathogens are covalently crosslinked to the fibrin network of leading to their immobilization and prevention of bacterial spreading. Therfore we suggested a general immune function for fXIII in addition to its role in hemostasis. The fXIII mediated entrapment within the clot was further investigated in experiments with the important human pathogen S. pyogenes. One of the main virulence factors of this pathogen, the Ml protein, was identified as one of the surface proteins of S. pyogenes, which is targeted by fXIII during bacterial entrapment. It has also been shown that the activation of the contact system on the surface of bacterial pathogens is leading to the generation of antimicrobial activity. Indeed, we showed that S. pyogenes bacteria are killed when incubated in activated plasma as well as within the clot. These data suggest the fXIII mediated immobilization of bacteria and the generation of antimicrobial acivity upon contact activation as a two-step mechanism during the early innate immune response against S. pyogenes. Using an experimental mouse infection model we showed that mice lacking fXIII develop more severe local signs of inflammation after subcutaneous infection with S. pyogenes when compared with wildtype animals. Interestingly, the treatment of infected mice with a human fXIII concentrate dampened the systemic dissemination of bacteria during the early time points of infection. In addition, we detected fXIII-mediated crosslinking of bacteria to the fibrin network in biopsies obtained from patients with severe S. pyogens infections, supporting the concept that coagulation and fXIII contribute to the early innate immune response against this pathogen.
Publications
- Pathogen Entrapment by Transglutaminase - A Conserved Early Innate Immune Mechanism. PLoS Pathogens 6(2): e1000763 (2010)
Wang, Z., Wilhelmsson, C., Hyrsl, P., Loof, T.G., Dobes, P., Klupp, M., Loseva, O., Mörgelin, M., Ikle, J., Gripps, R.M., Herwald, H., and Theopold, U.
- Coagulation systems of invertebrates and vertebrates and their roles in innate immunity: The same side of two coins? Journal of Innate Immunity 3(1): 34-40 (2011)
Loof, T.G., Schmidt, O., Herwald, H., and Theopold, U.
- Coagulation, an ancestral serine protease cascade, exerts a novel function in early innate immime defense. Blood Epub ahead of print May, 25th (2011)
Loof, T.G., Mörgelin, M., Johansson, L., Oehmcke, S., Olin, A.I., Dickneite, G., Norrby-Teglund, A., Theopold, U., and Herwald, H.
