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

Mary P Horn1, Sharmon M Knecht, Frances L Rushing

  • 1Ball State University, Muncie, IN, USA.

The Journal of Pharmacology and Experimental Therapeutics
|April 5, 2008
PubMed

Insights

Simvastatin, a statin, reduces sepsis risk by blocking Staphylococcus aureus invasion. It inhibits host cell invasion by affecting cholesterol biosynthesis and small GTPase localization, preventing bacterial entry.

Area of Science:

  • Microbiology
  • Cell Biology
  • Pharmacology

Background:

  • Patients on statin therapy exhibit a reduced risk of mortality from bacterial sepsis.
  • Staphylococcus aureus is a primary cause of sepsis, necessitating novel therapeutic strategies.
  • Host cell invasion by S. aureus is a critical step in sepsis pathogenesis.

Purpose of the Study:

  • To investigate the protective mechanism of simvastatin against S. aureus-induced sepsis.
  • To elucidate how simvastatin inhibits bacterial invasion of host cells.
  • To determine the role of cholesterol biosynthesis and small GTPases in simvastatin's protective effects.

Main Methods:

  • Assessing simvastatin's effect on S. aureus invasion in host cells.
  • Analyzing the impact of simvastatin on isoprenoid intermediates and small GTPase localization (CDC42, Rac, RhoB).
  • Investigating the role of phosphoinositide 3-kinase (PI3K) and its interaction with prenylated proteins.

Main Results:

  • Simvastatin inhibited S. aureus invasion by depleting isoprenoid intermediates, leading to cytosolic accumulation of CDC42, Rac, and RhoB.
  • Actin stress fiber disassembly, crucial for invasion, was attenuated by simvastatin and PI3K inhibition.
  • Simvastatin treatment sequestered the PI3K p85 isoform in the cytosol, preventing its interaction with prenylated small GTPases.

Conclusions:

  • Simvastatin protects against S. aureus sepsis by restricting PI3K p85 localization, thereby inhibiting actin dynamics essential for bacterial endocytosis.
  • This mechanism highlights a host-directed protective strategy against invasive S. aureus infections.
  • Targeting cholesterol biosynthesis and small GTPase signaling offers a potential therapeutic avenue for sepsis treatment.

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