Modification of host defense mechanisms in severe bacterial infectious diseases
Final Report Abstract
Microvesicles: We described that the interaction of pro-coagulant MVs with bacteria of the species Streptococcus pyogenes is part of the early immune response to the invading pathogen. As shown by negative staining electron microscopy and clotting assays, pro-coagulant MVs bind in the presence of plasma to the bacterial surface. Fibrinogen was identified as a linker that, through binding to the M1 protein of S. pyogenes, allows the opsonization of the bacteria by MVs. Surface plasmon resonance analysis revealed a strong interaction between pro-coagulant MVs and fibrinogen with a KD value in the nanomolar range. When performing a massspectrometry-based strategy to determine the protein quantity, a significant upregulation of the fibrinogen-binding integrins CD18 and CD11b on pro-coagulant MVs was recorded. Finally we show that plasma clots induced by pro-coagulant MVs are able to prevent bacterial dissemination and possess antimicrobial activity. These findings were confirmed by in vivo experiments, as local treatment with pro-coagulant MVs dampens bacterial spreading to other organs and improved survival in an invasive streptococcal mouse model of infection. Taken together, our data implicate that pro-coagulant MVs play an important role in the early response of the innate immune system in infectious diseases. The second study showed that a high amount of TF in septic patients is significantly associated with increased risk for disease severity, according to a high SAPS II score. Quantification of total MVs in plasma, independent from their cell origin, might be indicative for the outcome of patients in sepsis. Novel streptokinase-mediated virulence mechanisms of S. pyogenes: Our first study gives new insights into the mechanisms by which S. pyogenes triggers the human contact system and stresses the function of soluble and surface located plasmin exploited as a group A streptococcal virulence factor through the action of streptokinase. Our second study describes another novel streptokinase-mediated virulence mechanism that may contribute to the escape of S. pyogenes from the human innate immune system.
Publications
- (2013) A Novel Role for pro-coagulant microvesicles in the early host defense against Streptococcus pyogenes. PLoS Pathogens, 9(8) e1003529
Oehmcke, S., Westman, J., Malmström, J., Mörgelin, M., Olin, A. I., Kreikemeyer, B., & Herwald, H.
(See online at https://doi.org/10.1371/journal.ppat.1003529) - (2013). Modulation of the coagulation system during severe streptococcal disease. Book chapter: Host-Pathogen Interactions in Streptococcal Diseases. Curr. Top. Microbiol., 368: 189-205
Shannon, O., Herwald, H. and Oehmcke, S.
(See online at https://doi.org/10.1007/82_2012_283) - (2015). Streptococcus pyogenes triggers activation of the human contact system by streptokinase. Infect. Immun. IAI.00180-15
Nitzsche, R., Rosenheinrich, M., Kreikemeyer, B., and Oehmcke-Hecht, S.
(See online at https://doi.org/10.1128/IAI.00180-15) - (2016) Streptococcus pyogenes escape from extracellular histone killing through plasminogen binding and activation by streptokinase”, Journal of Innate Immunity 2016;8:589-600
Nitzsche, R., Köhler, J., Kreikemeyer, B. and Oehmcke-Hecht, S.
(See online at https://doi.org/10.1159/000448039) - (2016). High intravascular tissue factor - but not extracellular microvesicles - in septic patients is associated with a high SAPS II score. Journal of Intensive Care. 4: 34
Trepesch, C., Kreikemeyer, B., Glass, A., Schubert, J.K., and Oehmcke- Hecht, S.
(See online at https://dx.doi.org/10.1186/s40560-016-0160-5)
