Suppression of influenza A proliferation by inhibiting Myosin Light Chain phosphorylation

Abstract

Emergence of resistance to the drugs against influenza and inadequate flu vaccination coverage in human are cause for concern. Cytoskeleton plays crucial role in endocytosis of viruses by cells. We sought to determine if inhibition of Myosin Light Chian (MLC) phosphorylation blocks influenza virus proliferation. Our studies indicate that infection of cells with influenza increases the function of RhoA and Rho kinase proteins, accompanied by an increase in MLC‐phosphorylation and assembly of actin stress fibers. The inhibition of MLC phosphorylation via exposure of cells to Rho Kinase, MLC‐kinase, and protein kinase C inhibitors as well as statins resulted in suppression of influenza virus. In addition, Chelation of intracellular calcium or inhibition of calmodulin blocked the virus proliferation. Exposure of cells to all of the above mentioned inhibitors led to a reduction in MLC phosphorylation and actin stress fiber formation. In contrast, exposure of the cells to a protein kinase C agonist (Phorbol Myristate Acetate) led to induction of MLC phosphorylation and facilitation of influenza proliferation. Mechanism for inhibition of virus proliferation by all of the afore mentioned inhibitors including statins was blocking of influenza virus entry to the nucleus of host cell. Our studies for the first time provide compelling evidence for the role of MLC phosphorylation in proliferation of influenza virus.