Role of Extracellular Signal-Regulated Kinase (ERK) in New World Alphavirus Multiplication




Voss, Kelsey

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New World alphaviruses belonging to the family Togaviridae are known to infect humans and equines and cause encephalitic disease. The New World alphaviruses are classified as emerging infectious agents and Category B select agents. There are concentrated efforts dedicated to the development of medical countermeasures to New World alphavirus infections including therapeutics and vaccines. Our current study is focused on the role of the host extracellular signal-regulated kinase (ERK) in the infectious process of New World alphaviruses. We demonstrate that infection of human astrocytoma cells by Venezuelan equine encephalitis virus (VEEV) results in the activation of many signaling molecules of the ERK-signaling cascade. Inhibition of ERK1/2 by the small molecule inhibitor Ag-126 results in inhibition of viral multiplication. Time of addition studies reveal that Ag-126-mediated inhibition of VEEV occurs during early and later stages of the infectious process, likely affecting early, post-entry events and late, exit events. While our studies revealed that expression of viral structural proteins was modestly downregulated in Ag-126 treated cells, we did not observe any influence of Ag-126 on the nuclear and cytoplasmic distribution of the viral capsid protein. Studies focused on the survival of host cells in the presence of Ag-126 indicated an increased percentage of cells that survived the infection in the presence of Ag-126. Finally, extending our studies to virulent strains of VEEV, Eastern and Western equine encephalitis viruses (EEEV and WEEV) revealed that Ag-126 exerted a broad-spectrum inhibitory effect on New World alphavirus multiplication, thus indicating that the host kinase, ERK, is a broad-spectrum candidate for development of novel therapeutics against New World alphaviruses.



Alphaviruses, Host kinase, ERK, MAPK signalling, Antiviral