Mechanisms of cell death induction by Staphylococcus aureus in leucocytes and endothelial cells

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Staphylococcus aureus is a frequent human pathogen, which can induce a multitude of serious diseases, such as endocarditis, pneumonia, soft-tissue infections and septic shock. The course of infection is determined by various staphylococcal virulence factors, including the release of toxins, bacterial adhesion and host cell invasion. Only recently, different research groups, which applied murine disease models, have published conflicting results concerning the role of the S. aureus pore-forming toxins α-hemolysin (α-toxin) and Panton-Valentine leukocidin (PVL). Both toxins have been associated with severe necrotizing infections. They exhibit cytolytic effects, which are restricted to certain cell types; however, their mechanisms of action are largely unknown. This project is designed to investigate the impact of defined S. aureus virulence factors, with special regard to α-toxin and PVL, on human leucocytes and endothelial cells, which come into close contact to bacteria during endo- and perivascular infections. On the staphylococcal side additional factors will be explored, which act together with α-toxin and PVL and contribute to the infection process. On the host cell side receptors and signal transduction pathways will be analyzed, which are activated during the infection process and induce cell death. Detailed knowledge about the cytolytic activity of S. aureus provides new rationale for therapeutic intervention in severe S. aureus infections.