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- Loof, Torsten, et al.
(författare)
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Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:9, s. 2589-2598
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Tidskriftsartikel (refereegranskat)abstract
- Phylogenetically conserved serine protease cascades play an important role in invertebrate and vertebrate immunity. The mammalian coagulation system can be traced back some 400 million years and shares homology with ancestral serine proteinase cascades that are involved in, for example, Toll receptor signaling in insects and release of antimicrobial peptides during hemolymph clotting. In the present study, we show that the induction of coagulation by bacteria leads to immobilization and killing of Streptococcus pyogenes bacteria inside the clot. The entrapment is mediated via cross-linking of bacteria to fibrin fibers by the action of coagulation factor XIII (fXIII), an evolutionarily conserved transglutaminase. In a streptococcal skin infection model, fXIII(-/-) mice developed severe signs of patho-logic inflammation at the local site of infection, and fXIII treatment of wild-type animals dampened bacterial dissemination during early infection. Bacterial killing and cross-linking to fibrin networks was also detected in tissue biopsies from patients with streptococcal necrotizing fasciitis, supporting the concept that coagulation is part of the early innate immune system.
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| 3. |
- Loof, Torsten, et al.
(författare)
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Coagulation Systems of Invertebrates and Vertebrates and Their Roles in Innate Immunity : The Same Side of Two Coins?
- 2011
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 3:1, s. 34-40
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Forskningsöversikt (refereegranskat)abstract
- Bacterial infections represent a serious health care problem, and all multicellular organisms have developed defense mechanisms to eliminate pathogens that enter the host via different paths including wounds. Many invertebrates have an open circulatory system, and effective coagulation systems are in place to ensure fast and efficient closure of wounds. It was proposed early on that coagulation systems in invertebrates play a major role not only in sealing wounds but also in preventing systemic infections. More recent evidence suggests that vertebrates, too, rely on clotting as an immune effector mechanism. Here we discuss the evolution of clotting systems against the background of their versatile function in innate immunity. Copyright (C) 2010 S. Karger AG, Basel
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| 4. |
- Wang, Zhi, et al.
(författare)
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Pathogen Entrapment by Transglutaminase - A Conserved Early Innate Immune Mechanism
- 2010
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Ingår i: PLOS pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 6:2, s. e1000763-
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Tidskriftsartikel (refereegranskat)abstract
- Clotting systems are required in almost all animals to prevent loss of body fluids after injury. Here, we show that despite the risks associated with its systemic activation, clotting is a hitherto little appreciated branch of the immune system. We compared clotting of human blood and insect hemolymph to study the best-conserved component of clotting systems, namely the Drosophila enzyme transglutaminase and its vertebrate homologue Factor XIIIa. Using labelled artificial substrates we observe that transglutaminase activity from both Drosophila hemolymph and human blood accumulates on microbial surfaces, leading to their sequestration into the clot. Using both a human and a natural insect pathogen we provide functional proof for an immune function for transglutaminase (TG). Drosophila larvae with reduced TG levels show increased mortality after septic injury. The same larvae are also more susceptible to a natural infection involving entomopathogenic nematodes and their symbiotic bacteria while neither phagocytosis, phenoloxidase or-as previously shown-the Toll or imd pathway contribute to immunity. These results firmly establish the hemolymph/blood clot as an important effector of early innate immunity, which helps to prevent septic infections. These findings will help to guide further strategies to reduce the damaging effects of clotting and enhance its beneficial contribution to immune reactions.
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