Forschungsprojektförderung im Rahmen des Sonderfoschungsbereich 1009: Breaking Barriers (DFG; SFB 1009), Teilprojekt B01 "Mechanisms of Staphylococcus aureus to breach cellular barriers and to invade host tissue"
S. Niemann, G.Peters Dauer: 1.6.2012 - 30.6.2020
Staphylococcus aureus is a facultative pathogenic bacterium that often colonizes epithelial surfac-es of healthy individuals, but can also cause serious and life-threatening invasive infections, such as endocarditis, pneumonia, osteomyelitis and sepsis. The first critical step for S. aureus to establish these invasive infections is to breach the host epithelial and endothelial cell barriers and to penetrate into deeper tissue. S. aureus expresses a multitude of virulence factors, including sur-face proteins, toxins and other secreted compounds that have been described to contribute to dis-ease development. In this regard, we have previously reported the proinflammatory and cytotoxic effects of the pore-forming toxins -hemolysin and Panton-Valentine Leukocidin, which have been also associated with severe staphylococcal diseases. Nevertheless, a detailed knowledge of their mechanisms of action (e.g. receptor binding, induction of intracellular effects) is largely lack-ing and will be investigated in this project. Additionally, S. aureus is increasingly recognized as a facultative intracellular pathogen. S. aureus can express several surface proteins with adhesive functions (called adhesins) that interact with components of the extracellular matrix or with recep-tors expressed by the host cells, which facilitate its internalization within the host cells. We have demonstrated that S. aureus can internalize in various types of host cells, including epithelial and endothelial cells and we found that the subsequent post-invasion events are highly strain- and host cell-specific. On the one hand they are depending on the staphylococcal virulence factor ex-pression within the intracellular location, which can induce bacterial transmigration, activation/modulation of the host immune response and cytotoxic reactions. On the other hand, also non-professional phagocytes, including epithelial and endothelial cells, are endowed with many defence mechanisms, such as degradation of bacteria or activation of the host immune system. The aim of this proposal is to identify important staphylococcal virulence factors, which enable the bacteria to breach cellular barriers, to escape the host defence system and establish deep tissue in-fections. A detailed knowledge of the S. aureus interaction with the host cell (e.g., cellular recep-tors for toxins and bacterial strategies to transmigrate epithelial/endothelial barriers) is the prerequisite to develop new antiinfective strategies against S. aureus.