beta 1-containing adhesions at the plasma membrane function as dynamic complexes to provide bidirectional communication between the cell and its environment, yet commonly are used by pathogens to gain host cell entry Recently. the cholesterol-lowering drug simvastatin was found to inhibit host invasion through beta 1-containing adhesion complexes To better understand the regulatory mechanisms controlling adhesion formation and Uptake and the Use of these complexes by Staphylococcus aureus, the primary etiologic agent in sepsis, bacteremia and endocarditis, we investigated the mechanism of inhibition by simvastatin In response to simvastatin, adhesion complexes diminished as well as beta 1 trafficking to the plasma membrane required to initiate adhesion formation Simvastatin stimulated CDC42 activation and coupling to p85, a small-guanosine triphosphatase (GTPase) activating protein (GAP), yet sequestered CDC42 coupled to p85 within the cytosol. Loss of p85 GAP activity through use of genetic strategies decreased host cell invasion as well as beta 1 trafficking From these findings, we propose a mechanism whereby p85 CAP activity localized within membrane compartments facilitates beta 1 trafficking By sequestering p85 within the cytosol. simvastatin restricts the availability and uptake of the receptor used by pathogenic strains to gain host cell entry. (C) 2009 Elsevier Inc All rights reserved