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

dc.contributor.advisorNarayanan, Aarthi
dc.contributor.authorVoss, Kelsey
dc.creatorVoss, Kelsey
dc.date2014-07-30
dc.date.accessioned2014-10-21T20:33:16Z
dc.date.available2015-02-11T20:00:52Z
dc.date.issued2014-10-21
dc.description.abstractNew 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.
dc.description.noteThis thesis was embargoed by the author and will not be available until January 30, 2015.
dc.identifier.urihttps://hdl.handle.net/1920/9093
dc.language.isoen_US
dc.rightsCopyright 2014 Kelsey Voss
dc.subjectAlphaviruses
dc.subjectHost kinase
dc.subjectERK
dc.subjectMAPK signalling
dc.subjectAntiviral
dc.titleRole of Extracellular Signal-Regulated Kinase (ERK) in New World Alphavirus Multiplication
dc.typeThesis
thesis.degree.disciplineBiology
thesis.degree.grantorGeorge Mason University
thesis.degree.levelMaster's
thesis.degree.nameMaster of Science in Biology

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