Receptor-mediated intercellular interactions pertinent to infection and inflammation under shear

Receptor-mediated cell adhesion plays a pivotal role in diverse biological processes that occur in the vasculature including infection and inflammation. A critical step in polymorphonuclear-leukocyte (PMN) recruitment to sites of inflammation/infection is their adhesion to activated endothelium. Also, evidence suggests that initiation of endovascular infections and subsequent bacterial metastasis is enhanced by platelet-bacterial cell interactions. Since these interactions occur in the fluid-mechanical environment of the vasculature, it is important to characterize the molecular mechanisms mediating cell adhesion under physiologically relevant flow conditions. Therefore, we examined the effect of hydrodynamic shear on interactions of platelets with Staphylococcus aureus (S. aureus) cells (pertinent to infection) and those of PMNs with selectin substrates (pertinent to inflammation) using experimental and computational methods.; The first part of the study comprises of an in-vitro experimental investigation of the effect of fluid-shear on the kinetics and receptor specificity of platelet- S. aureus adhesive interactions in cell suspensions using a rheometric-flow-cytometric methodology. We demonstrate that shear-induced collisions augment platelet- S.aureus binding, which is further potentiated by platelet-activation with stromal-derived-factor-1beta. The molecular interaction of platelet alpha IIbbeta3 with bacterial clumping-factor-A through fibrinogen-bridging is necessary for stable binding. Although this pathway is sufficient at low shear (<400 s-1), the involvement of platelet GPIb and staphylococcal-protein-A (SPA) through von-Willebrand-factor (VWF)-bridging is essential for optimal recruitment of S. aureus by platelets at high shear. Thus, platelet-activation and hydrodynamic shear affect platelet-S. aureus adhesive interactions pertinent to the process of S. aureus -induced bloodstream-infections.; In the second part of the study, we developed a mathematical model to simulate PSGL-1-mediated rolling of a deformable PMN on a P-selectin-coated surface under shear flow. Our simulations predict that catch-slip bond behavior and to a lesser extent cell deformation are responsible for the shear threshold phenomenon. Cells bearing viscoelastic rather than rigid microvilli roll slower only at high P-selectin densities and elevated levels of shear (≥400 s -1). Our model demonstrates that cell-rolling is a highly coordinated process influenced by three distinct length scales---cell deformation, microvillus viscoelasticity, and receptor-ligand binding kinetics.; Collectively, these findings may provide insights for the rational development of novel therapeutics to combat infection and inflammation.