Abstract 147: Statins Block Influenza Infection By Down-regulating Rho/rho Kinase Pathway
Influenza infection can trigger myocardial infarction and sudden cardiac death. Vaccination against influenza prevents several cardiovascular events and has been recently recommended by American Heart Association for secondary prevention. Many beneficial, non-lipid lowering effects of statins occur as a result of their ability to inhibit Rho GTPase proteins activation. Recent data suggest that statins block HIV-1 replication. We tested the hypothesis that statins inhibit the proliferation of influenza virus through inhibition of Rho/Rho kinase pathway. Using several standard virological techniques including quantitative real-time PCR, we demonstrated that statins (atorvastatin, 20 mM and rusovastatin, 20 mM) inhibit the proliferation of influenza A (strains- H3N2 and H1N1) virus in Madin-Darby Canine Kidney (MDCK) cells. The inhibition was dose-dependent and was blocked by addition of mevalonate but not cholesterol. Influenza infection resulted in increased activation of RhoA GTPase protein in MDCK cells. This effect was blocked by statins but circumvented by mevalonate. Addition of a product of cholesterol synthesis, geranylgeranyl pyrophosphate which prenylates and activates Rho proteins blocked the inhibitory action of both statins. Furthermore, treatment of infected cells with a geranylgeranyl transferase inhibitor but not a farnesyl transferase inhibitor suppressed the virus proliferation. Inhibition of Rho-associated kinase, an effecter of Rho A protein via the chemical inhibitors (Fasudil and Y27632) blocked the virus proliferation in a dose dependent manner, suggesting a crucial role for Rho/Rho kinase pathway in virus proliferation. Atorvastatin (40 mg/kg/day) reduced the lung virus titers and mortality in C57BL/6 mice infected with influenza A virus. Statins exert direct anti-influenza effects by down-regulating Rho/Rho kinase pathway. The effect of statins against influenza could explain part of their protective effects against cardiovascular events.