Fluid Shear Regulates the Kinetics and Receptor Specificity of Staphylococcus aureus Binding to Activated Platelets

Abstract

The interaction between surface components on the invading pathogen and host cells such as platelets plays a key role in the regulation of endovascular infections. However, the mechanisms mediating Staphylococcus aureus binding to platelets under shear remain largely unknown. This study was designed to investigate the kinetics and molecular requirements of platelet-S. aureus interactions in bulk suspensions subjected to a uniform shear field. Hydrodynamic shear-induced collisions augment platelet-S. aureus binding, which is further potentiated by platelet activation with stromal derived factor-1β. Peak adhesion efficiency occurs at low shear (100 s−1) and decreases with increasing shear. The molecular interaction of platelet αIIbβ3 with bacterial clumping factor A through fibrinogen bridging is necessary for stable bacterial binding to activated platelets under shear. Although this pathway is sufficient at low shear (≤400 s−1), the involvement of platelet gpIb and staphylococcal protein A through von Willebrand factor bridging is essential for optimal recruitment of S. aureus cells by platelets in the high shear regime. IgG plays an inhibitory role in the adhesion process, presumably by interfering with the binding of von Willebrand factor to staphylococcal protein A. This study demonstrates that platelet activation and a fluid-mechanical environment representative of the vasculature affect platelet-S. aureus cell-adhesive interactions pertinent to the process of S. aureus-induced bloodstream infections.

Klebsiella pneumoniae Flocculation Dynamics

“…Aggregation phenomena occur in a wide range of fields and the basic mathematical model for such phenomena, the Smoluchowski coagulation equations 1 , has been employed in such disparate fields as aerosols [7], meteorology [17], chemically dispersive systems [24], algal dynamics [2,18], immunology [13], and planetesimal evolution [11]. The seminal ideas were originally developed in the early 1900's by von Smoluchowski to model the rapid aggregation of colloids.…”

“…The fit, however, left much to be desired, and thus in the absence of higher resolution measurements, we assumed a bi-exponential for the shape of the initial density (13) Since we know the initial biomass B 1 , we can identify C 1 (14) To identify the other three parameters, we minimized over γ 1 , C 2 , and γ 2 , where b 0 is defined in (13) and C 1 is defined in (14). We employed the sequential quadratic programming method with inequality constraints and BFGS Hessian update in Matlab's fmincon, supplying it with the analytically computed gradient.…”

Platelet-Bacterial Interactions as Therapeutic Targets in Infective Endocarditis

“…All of the early S. aureus studies were carried out under static or non-physiological stirring conditions and therefore it is difficult to relate these studies to the disease processes. Studies using a cone and plate viscometer (a device that shears cells at a given flow rate) have demonstrated that protein A, ClfA, SdrC, SdrD and SdrE are important in thrombus formation (George et al, 2007;George et al, 2006;Pawar et al, 2004). However, extremely high shear rates were used in these rheological studies.…”

“…Platelets express a high affinity vonWillebrand factor receptor called GPIbα (Andrews et al, 2003). Under very high shear conditions, Pawar and colleagues demonstrated that deletion of SpA from S. aureus significantly reduced its interaction with platelets (Pawar et al, 2004). Furthermore, preincubating platelet rich plasma with a vonWillebrand Factor antibody or indeed blocking the platelet GPIbα receptor with an inhibitory monoclonal antibody partially inhibited the platelet-S. aureus interaction (Pawar et al, 2004 Serine rich protein SraP is a 227kDa large protein and a member of the highly conserved family of serine rich surface glycoproteins expressed on the cell wall of S. aureus .…”

“…Under very high shear conditions, Pawar and colleagues demonstrated that deletion of SpA from S. aureus significantly reduced its interaction with platelets (Pawar et al, 2004). Furthermore, preincubating platelet rich plasma with a vonWillebrand Factor antibody or indeed blocking the platelet GPIbα receptor with an inhibitory monoclonal antibody partially inhibited the platelet-S. aureus interaction (Pawar et al, 2004 Serine rich protein SraP is a 227kDa large protein and a member of the highly conserved family of serine rich surface glycoproteins expressed on the cell wall of S. aureus . A mutant strain of S. aureus lacking expression of SraP displayed signs of reduced virulence in a rabbit model of infective endocarditis, implicating its role in the development of a growing thrombus on a cardiac valve.…”