Effects of HSV-1 infection on disparate cell signaling pathways Public Deposited

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  • March 20, 2019
Creator
  • Gregory, Devon Arch
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Herpes simplex virus (HSV) commandeers cellular machinery in order to replicate. Two pathways which are utilized by the virus are the NFκB pathway and the DNA double strand break (DSB) response. The NFκB pathway is activated in a sustained manner following infection. This activation leads to a suppression of apoptosis in certain cell types and may also assist in viral gene expression. The most common route of activation for NFκB is through the IKK complex and IκB. This dissertation examines the NFκB pathway upstream of IκB, characterizing the role of IKKα and IKKβ, the two kinase subunits of the IKK complex. Both were found to be necessary for NFκB activation, though at different junctions in the pathway. Potential upstream effectors of the IKK complex are also characterized. PKR, NIK and Tak1 are kinases that activate the IKK complex following various normal cellular stimuli. None play a role in activation following HSV infection however, suggesting a unique method of activation by HSV. The cellular DSB response normally recognizes breaks in cellular DNA in order to repair the damage and initiate cell cycle arrest or apoptosis to maintain the integrity of the cell and organism. This dissertation examines the machinery involved in the initial detection and signaling of the DSB response following HSV infection. HSV activates the DSB response dependent upon viral DNA replication. Though downstream signaling in the pathway is not essential for viral replication, it does contribute to the efficacy of replication. Curiously, Mre11 was seen to be lost following infection. Mre11 is a component of the MRN complex which initially detects DSBs. Its loss suggests that the DSB response is inhibited and so the mechanism for its loss was pursued. Mre11 loss was not dependent upon ICP0, nor the activities of the proteasome or lysosome. Viral DNA replication was required for Mre11 loss, though not late gene expression. Mre11 loss was observed following activation of the DSB response with camptothecin, suggesting that its loss following infection is a result of an endogenous cellular mechanism.
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Advisor
  • Bachenheimer, Steven L.
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