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Novel roles of hemostatic proteins in human defence responses towards bacteria

Projectomschrijving

Na beschadiging van een bloedvat wordt het bloedstollingsysteem opgestart wat leidt tot afsluiting van de beschadiging en voorkomt daardoor onnodig bloedverlies. Echter, het bloedstollingsysteem is ook betrokken bij de afweer tegen bacteriën. In dit project bestuderen de onderzoekers de interactie tussen bacteriën en twee eiwitten van de bloedstolling waarvan tot voor kort nog niet bekend was dat ze ook betrokken waren bij de afweer tegen infecties. Via laboratoriumproeven en dierexperimentele aanpak wordt bestudeerd wat de gevolgen zijn van de interactie van deze twee stoleiwitten met bacteriën voor de werking van het stollingssysteem en de afweer tegen infecties, maar ook hoe bacteriën gebruik kunnen maken van eiwitten van de gastheer om de infectie bevorderen. Een beter begrip van de wisselwerking tussen bloedstolling en afweer kan leiden tot inzichten hoe in de toekomst de afweer van de gastheer tegen infecties verbeterd zou kunnen worden.

Producten

Titel: Beta2-glycoprotein I: evolution, structure and function
Auteur: Ph.G. de Groot, J.C.M. Meijers
Magazine: Journal of Thrombosis and Haemostasis
Titel: Induction of anti-beta2-glycoprotein I autoantibodies in mice by protein H of Streptococcus pyogenes
Auteur: G.M.A. van Os, J.C.M. Meijers, C. Agar, M.V. Seron, J.A. Marquart, P. Akesson, R.T. Urbanus, R.H.W.M. Derksen, H. Herwald, M. Morgelin, P.G. de Groot
Magazine: Journal of Thrombosis and Haemostasis
Titel: Beta2-glycoprotein I is incorrectly named apolipoprotein H
Auteur: C. Agar, P.G. de Groot, J.H.M. Levels, J.A. Marquart, J.C.M. Meijers
Magazine: Journal of Thrombosis and Haemostasis
Titel: Detection of lupus anticoagulant in the presence of rivaroxaban using Taipan snake venom time
Auteur: G.M.A. van Os, B. de Laat, P.W. Kamphuisen, J.C.M. Meijers, Ph.G. de Groot
Magazine: Journal of Thrombosis and Haemostasis
Titel: Recent Developments in Thrombin-Activatable Fibrinolysis Inhibitor
Auteur: P.F. Marx, C.J.N. Verkleij, M. Valls Seron, J.C.M. Meijers
Magazine: Mini-Reviews in Medical Chemistry
Titel: Thrombin-activatable fibrinolysis inhibitor is degraded by Salmonella enterica and Yersinia pestis
Auteur: M. Valls Seron, J. Haiko, Ph.G. de Groot, T.K. Korhonen, J.C.M. Meijers
Magazine: Journal of Thrombosis and Haemostasis
Titel: Evolutionary conservation of the lipopolysaccharide binding site of beta2-glycoprotein I
Auteur: C. Agar, P.G. de Groot, J.A. Marquart, J.C.M. Meijers
Magazine: Thrombosis and Haemostasis
Titel: Antiphospholipid syndrome. Current insights into laboratory diagnosis and pathophysiology
Auteur: G.M.A. van Os, R.T. Urbanus, J.C.M. Meijers, P.G. de Groot
Magazine: Hamostaseologie
Titel: Protein C inhibitor - A novel antimicrobial agent
Auteur: E. Malmström, M. Mörgelin, M. Malmsten, L. Johansson, A. Norrby-Teglund, O. Shannon, A. Schmidtchen, J.C.M. Meijers, H. Herwald
Magazine: PLoS Pathogens
Titel: Binding characteristics of thrombin-activatable fibrinolysis inhibitor to streptococcal surface collagen-like proteins A and B
Auteur: M. Valls Seron, T. Plug, J.A. Marquart, P.F. Marx, H. Herwald, Ph.G. de Groot, J.C.M. Meijers
Magazine: Thrombosis and Haemostasis
Titel: Beta2-glycoprotein I: a novel component of innate immunity
Auteur: C. Agar, Ph.G. de Groot, M. Mörgelin, S.D.D.C. Monk, G.M.A. van Os, J.H.M. Levels, B. de Laat, R.T. Urbanus, H. Herwald, T. van der Poll, J.C.M. Meijers
Magazine: BLOOD
Titel: Beta2-glycoprotein I can exist in two conformations: implications for our understanding of the antiphospholipid syndrome
Auteur: C. Agar, G.M.A. van Os, M. Morgelin, R.R. Sprenger, J.A. Marquart, R.T. Urbanus, R.H.W.M. Derksen, J.C.M. Meijers, Ph.G. de Groot
Magazine: BLOOD
Titel: Thrombin-Activatable Fibrinolysis Inhibitor and Bacterial Infections
Auteur: Mercedes Valls Serón
Titel: Beta2-glycoprotein I in innate immunity
Auteur: Cetin Agar
Titel: Development of auto-antibodies towards beta2-glycoprotein I in the antiphospholipid syndrome
Auteur: Gwendolyn M.A. van Os

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Samenvatting van de aanvraag

Bacterial infections are still a major clinical problem, which will rapidly expand by the emerging and spreading of antibiotic resistance. This emphasizes the need for alternative treatments. During bacterial infections, the host can respond with a number of different defence mechanisms, of which a hemostatic reaction is a prominent one. However, some bacteria can compromise the hemostatic responses, which will result in an unbridled infectious response with serious complications. In addition, in severe infections, such as sepsis and septic shock, the bacteria distort the pro-coagulant/anti-coagulant equilibrium, causing severe thrombotic or bleeding disorders. The goal of the present study is to understand how the coagulation and fibrinolytic systems modulate host-parasite interactions, by using in vitro, ex vivo, and in vivo models. A general screening of the interaction of clotting factors with Streptococcus pyogenes, an important human pathogen, established novel interactions of two proteins of the hemostatic system, thrombin-activatable fibrinolysis inhibitor (TAFI) and beta2-glycoprotein I (B2GPI) with the bacteria. TAFI is a procarboxypeptidase that links the coagulation and fibrinolytic systems, and it can regulate the inflammatory response. B2GPI is the principal antigen for the autoantibodies that cause the antiphospholipid sydrome, the most common acquired risk factor for thrombo-embolic complications. PMN-derived peptides from B2GPI displayed potent antimicrobial activity. We have established the binding site for TAFI and B2GPI on S. pyogenes to be SclA/B and protein H, respectively. We propose to study the interaction between the bacterial proteins and the hemostatic proteins in detail by cloning and expression of the bacterial surface proteins involved in the binding of TAFI and B2GPI in vitro. The affinity of interaction and characterization of the binding epitopes will be established with surface plasmon resonance. The functional consequences of the binding of the hemostatic proteins will be studied with isolated bacterial proteins and (mutant) bacterial strains. Changes in activation, activity and stability of TAFI and B2GPI after interaction with bacteria or bacterial proteins will be investigated in vitro. The importance of TAFI and B2GPI in the encapsulation of bacteria by fibrin will be investigated in vitro. The influence of TAFI and B2GPI on bacterial growth will be studied in mice overexpressing TAFI and B2GPI with wild-type and mutant bacterial strains. Biopsies of patients with invasive skin infections are available to visualise the presence of TAFI and B2GPI in complex with bacteria with light and electron microscopy. Plasma samples from patients with sepsis are available to measure the influence of bacterial infections on the distortion of the hemostatic balance and the roles of B2GPI and TAFI herein. The presence of antibodies towards the identified bacterial surface proteins will be tested in a large cohort of well-characterized patients with autoimmune antibodies, in order to search for a relation between bacterial infections and the occurrence of autoantibodies. The objective of this grant proposal is to elucidate the underexposed but important role of the hemostatic system in the human defence against bacterial infections, in order to explore the possibility of new antibacterial strategies. The strength of this grant proposal is that there is already a strong collaboration between the applying laboratories and that the role of both TAFI and B2GPI in hemostasis has been studied in detail in the past in the laboratories of the applicants. A number of important tools and reagents, including transgenic mice overexpressing human TAFI or B2GPI, have been generated by the applicants. Extensive expertise with S. pyogenes and its surface proteins is obtained via collaboration with Dr. H. Herwald from the University of Lund, Sweden. Therefore, a wealth of expertise and tools are available for the successful completion of this proposal. We postulate that elucidation of the functional, structural and clinical aspects of the interactions of hemostatic proteins with bacteria may lead to the identification of novel pathophysiological mechanisms and to the development of new therapeutical strategies.

Onderwerpen

Kenmerken

Projectnummer:
91207002
Looptijd: 100%
Looptijd: 100 %
2007
2011
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. J.C.M. Meijers
Verantwoordelijke organisatie:
Amsterdam UMC - locatie AMC