Simvastatin inhibits Staphylococcus aureus host cell invasion through modulation of isoprenoid intermediates

被引：41

作者：

Horn, Mary P. ^{[1
]}

Knecht, Sharmon M. ^{[1
]}

Rushing, Frances L. ^{[1
]}

Birdsong, Julie ^{[1
]}

Siddall, C. Parker ^{[1
]}

Johnson, Charron M. ^{[1
]}

Abraham, Terri N. ^{[1
]}

Brown, Amy ^{[1
]}

Volk, Catherine B. ^{[1
]}

Gammon, Kelly ^{[1
]}

Bishop, Derron L. ^{[2
]}

McKillip, John L. ^{[1
]}

McDowell, Susan A. ^{[1
]}

机构：

[1] Ball State Univ, Muncie, IN 47306 USA

[2] Indiana Sch Med, Muncie, IN USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2008年 / 326卷 / 01期

关键词：

D O I：

10.1124/jpet.108.137927

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：135 / 143

页数：9

共 40 条

[1] Cellular invasion by Staphylococcus aureus reveals a functional link between focal adhesion kinase and cortactin in integrin-mediated internalisation [J].