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.
