The broad objective of the proposed research is to comprehensively characterize the molecular interactions between Staphylococcus aureus and platelets as a function of the dynamic shear environment in order to provide a rational basis for the development of novel treatments to combat staphylococcal cardiovascular infections. The hypothesis to be tested is that shear stress affects the adhesive interactions between platelets and S. aureus by modulating the (i) relative importance of the adhesive molecules involved and (ii) the reaction binding kinetics. The proposed approach uses controlled, dynamic, in vitro experimental systems to systematically and comprehensively examine the importance of platelet activation, blood components, blood flow, and bacteria in the development of blood-born staphylococcal infections. A long-term goal of this work is to investigate the interrelationship between thrombogenesis and cardiovascular infection mechanisms.
The specific aims of the project are to: 1) comprehensively elucidate the molecular mechanisms of S. aureus-platelet interactions under shear conditions of direct physiological relevance; 2) characterize S. aureus-platelet heteroaggregation in cell suspensions subjected to controlled levels of shear and; 3) develop a protocol to study S. aureus-platelet aggregation in whole blood and to evaluate the effect of this extension on S. aureus-platelet interactions under shear conditions. Completion of these specific aims will provide a rational basis for the design of new therapeutic molecules to block specific adhesion events, as well as identify the most important bacterial receptors to target in vaccine development.
|Johnson, Michael A; Ross, Julia M (2008) Staphylococcal presence alters thrombus formation under physiological shear conditions in whole blood studies. Ann Biomed Eng 36:349-55|
|George, Niraj Procopio Evagrio; Konstantopoulos, Konstantinos; Ross, Julia Myers (2007) Differential kinetics and molecular recognition mechanisms involved in early versus late growth phase Staphylococcus aureus cell binding to platelet layers under physiological shear conditions. J Infect Dis 196:639-46|
|George, Niraj Procopio Evagrio; Wei, Qi; Shin, Pyong Kyun et al. (2006) Staphylococcus aureus adhesion via Spa, ClfA, and SdrCDE to immobilized platelets demonstrates shear-dependent behavior. Arterioscler Thromb Vasc Biol 26:2394-400|
|Nandakumar, Renu; Nandakumar, M P; Marten, Mark R et al. (2005) Proteome analysis of membrane and cell wall associated proteins from Staphylococcus aureus. J Proteome Res 4:250-7|
|Shin, Pyong Kyun; Pawar, Parag; Konstantopoulos, Konstantinos et al. (2005) Characteristics of new Staphylococcus aureus-RBC adhesion mechanism independent of fibrinogen and IgG under hydrodynamic shear conditions. Am J Physiol Cell Physiol 289:C727-34|
|Mascari, Lisa M; Ross, Julia M (2003) Quantification of staphylococcal-collagen binding interactions in whole blood by use of a confocal microscopy shear-adhesion assay. J Infect Dis 188:98-107|
|Hall, Andrea E; Domanski, Paul J; Patel, Pratiksha R et al. (2003) Characterization of a protective monoclonal antibody recognizing Staphylococcus aureus MSCRAMM protein clumping factor A. Infect Immun 71:6864-70|