Abstract
Influenza A viruses are a severe threat worldwide, causing large epidemics that kill thousands every year. Prevention of influenza infection is complicated by continuous viral antigenic changes. Newer anti-influenza agents include MEK/ERK and protein kinase C inhibitors; however, the downstream effectors of these pathways have not been determined. In this study, we identified a common mechanism for the inhibitory effects of a significant group of anti-influenza agents. Our studies showed that influenza infection activates a series of signaling pathways that converge to induce myosin light chain (MLC) phosphorylation and remodeling of the actin cytoskeleton. Inhibiting MLC phosphorylation by blocking RhoA/Rho kinase, phospholipase C/protein kinase C, and HRas/Raf/MEK/ERK pathways with the use of genetic or chemical manipulation leads to the inhibition of influenza proliferation. In contrast, the induction of MLC phosphorylation enhances influenza proliferation, as does activation of the HRas/Raf/MEK/ERK signaling pathway. This effect is attenuated by inhibiting MLC phosphorylation. Additionally, in intracellular trafficking studies, we found that the nuclear export of influenza ribonucleoprotein depends on MLC phosphorylation. Our studies provide evidence that modulation of MLC phosphorylation is an underlying mechanism for the inhibitory effects of many anti-influenza compounds.
Highlights
The emergence of highly contagious influenza A virus strains, such as the new H1N1 swine influenza, is a serious threat to global human health
Influenza A virus infects and replicates in HUVECs the Madin Darby canine kidney (MDCK) cell line is most commonly used for influenza studies, we and others have shown that the influenza virus infects and replicates in human umbilical vein endothelial cells (HUVECs) [26,27]
We have shown that influenza infection activates the signaling pathways that converge to induce myosin light chain (MLC) phosphorylation and actin cytoskeleton remodeling
Summary
The emergence of highly contagious influenza A virus strains, such as the new H1N1 swine influenza, is a serious threat to global human health. A high frequency of resistance in clinical isolates in the United States has led to the conclusion that M2 inhibitors should not be used for the prevention or treatment of influenza until susceptibility to these drugs has been re-established among circulating influenza A isolates [1] Because of their relatively small genomic coding capacity, influenza A viruses extensively manipulate and exploit host cell functions to support viral replication. Targeting cellular proteins required for influenza replication is a valuable alternative for preventing and treating infections This approach is advantageous in that the development of drug resistance is unlikely and the drugs target common pathways used by human, avian, and other influenza viruses. Activation of RhoA leads to the stimulation of Rho-kinase, which, in turn, phosphorylates the regulatory myosin-binding subunit of MLCP, resulting in the inhibition of MLCP. PKG inhibits MLC phosphorylation by reducing intracellular Ca+2 levels and activating MLCP [3,9]
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