title: Simvastatin inhibits Staphylococcus aureus host cell invasion through modulation of isoprenoid intermediates.
abstract: Patients on a statin regimen have a decreased risk of death due to bacterial sepsis. We have found that protection by simvastatin includes the inhibition of host cell invasion by Staphylococcus aureus, the most common etiologic agent of sepsis. Inhibition was due in part to depletion of isoprenoid intermediates within the cholesterol biosynthesis pathway and led to the cytosolic accumulation of the small GTPases CDC42, Rac, and RhoB. Actin stress fiber disassembly required for host invasion was attenuated by simvastatin and by the inhibition of phosphoinositide 3-kinase (PI3K) activity. PI3K relies on coupling to prenylated proteins, such as this subset of small GTPases, for access to membrane-bound phosphoinositide to mediate stress fiber disassembly. Therefore, we examined whether simvastatin restricts PI3K cellular localization. In response to simvastatin, the PI3K isoform p85, coupled to these small-GTPases, was sequestered within the cytosol. From these findings, we propose a mechanism whereby simvastatin restricts p85 localization, inhibiting the actin dynamics required for bacterial endocytosis. This approach may provide the basis for protection at the level of the host in invasive infections by S. aureus.
authors.affiliation: Ball State University, Muncie, IN, USA.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Horn
authors.forename: Sharmon M
authors.initials: SM
authors.lastname: Knecht
authors.forename: Frances L
authors.initials: FL
authors.lastname: Rushing
authors.forename: Julie
authors.initials: J
authors.lastname: Birdsong
authors.forename: C Parker
authors.initials: CP
authors.lastname: Siddall
authors.forename: Charron M
authors.initials: CM
authors.lastname: Johnson
authors.forename: Terri N
authors.initials: TN
authors.lastname: Abraham
authors.forename: Amy
authors.initials: A
authors.lastname: Brown
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Volk
authors.forename: Kelly
authors.initials: K
authors.lastname: Gammon
authors.forename: Derron L
authors.initials: DL
authors.lastname: Bishop
authors.forename: John L
authors.initials: JL
authors.lastname: McKillip
authors.forename: Susan A
authors.initials: SA
authors.lastname: McDowell
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D034982:Integration Host Factors / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019821:Simvastatin / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000166:cytology / Q000187:drug effects*; D013729:Terpenes / Q000378:metabolism*
chemical_list: D034982:Integration Host Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019821:Simvastatin; D013729:Terpenes