The role of endothelial cell receptors and bacterial products in Staphylococcus aureus endovascular infection and novel strategies for anti-inflammatory interventions

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Tissue infiltration by pathogenic bacteria depends on interactions with the extracellular matrix and/or cell suface or cell-associated adhesive components of the host. Vascular entry of Gram-positive bacteria causing endocarditis or non-healing wounds includes further interactions with soluble host components providing an overall defense evasion strategy. Here, new anti-inflammatory components of S. aureus and their role in host defense as well as the concept of host scavenger molecules in the vasculature for bacterial recognition will be studied in vitro and in vivo: i) S. aureus releases certain extracellular adhesion products (Eap), relevant for bacterial adherence, but also being bacteria-pro-tective against the inflammatory response due to inhibition of the host´s leukocyte recruitment machinery (previous studies). The underlying molecular mechanisms of Eap functions will be dis-sected and evaluated in in vitro and in vivo models; the use of Eap as new anti-inflammatory drug will be considered. ii) Novel host Eap "receptors" will be identified by a combined approach using phage displayed single-chain antibodies and proteome analysis. iii) The contribution of the endothelial cell "receptor for advanced glycation endproducts" (RAGE) in recognition of (AGE-)S. aureus, bacterial entry and inflammation will be studied utilizing molecular genetic approaches and animal models of vascular diseases, allowing to evaluate new anti-adhesion strategies for anti-microbial therapy.