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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.

Mouse soleus muscles were denervated by crushing the soleus nerve where it enters the muscle to determine if denervation followed by self-reinnervation can permanently alter the mix of fiber types in a muscle. Reinnervated and contralateral control muscles were sectioned at 2 and 7 months postdenervation and histochemically stained for myosin ATPase to determine the percentages of fast and slow twitch fibers in the muscles. It was found that, at both 2 and 7 months postdenervation, reinnervated muscles had a significantly higher percentage of slow twitch fibers than did contralateral control muscles (86.7 versus 67.8% at 2 months and 90.0 versus 69.3% at 7 months). Soleus muscles were also denervated by crushing the soleus nerve where it exits the gastrocnemius muscle (approximately 4 mm proximal to where the nerve enters the soleus muscle) to ascertain if the location of the nerve lesion plays a role in the ultimate outcome of the process of self-reinnervation. Reinnervated muscles and their contralateral muscles were sectioned at 2 months postdenervation and histochemically stained for myosin ATPase as before. It was found that, in contrast to muscles denervated at the point of nerve entry, muscles denervated 4 mm more proximal exhibited only a small increase in their percentage of slow twitch fibers which was not statistically significant (71.4 versus 68.4%). These results suggest that denervation followed by self-reinnervation can cause a permanent change in a muscle's fiber type mix and that the location of the nerve lesion strongly influences the final outcome of the reinnervation process.