Date of Award

Summer 8-23-2019

Level of Access

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

Advisor

Melissa Maginnis

Second Committee Member

Julie Gosse

Third Committee Member

Robert Gundersen

Additional Committee Members

Robert Wheeler

Samuel Hess

Abstract

As obligate intracellular parasites, viruses must infect a host-cell and requisition cellular machinery for viral replication. JC polyomavirus (JCPyV) is a ubiquitous human pathogen that can cause a lytic infection in glial cells of the central nervous system in immunocompromised individuals. In order to initiate infection however, the virus must alter prototypical cellular processes that promote cellular homeostasis. The main driver of these processes are signaling pathways, the means by which the cell interacts and responds to the extracellular environment. Many signaling cascades are responsible for promoting growth, responding to pathogens, initiating differentiation, or inducing cell death. Through the works described herein, I have discovered that JCPyV utilizes the mitogen-activated protein kinase, extracellular signal-regulated kinase (MAPK-ERK) cascade, to facilitate infection. These works sought to characterize how JCPyV, the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML), usurps MAPK-ERK signaling to promote infectious processes. Prior to these works, little was known about JCPyV manipulation of cellular signaling cascades. Our work has demonstrated that each of the core kinases that comprise the MAPK-ERK pathway: Raf, MEK, and ERK, are required for successful JCPyV infection. The terminal protein of this cascade, ERK, can activate hundreds of cellular substrates including transcription factors (TFs) upon phosphorylation under normal conditions. During viral challenge, JCPyV induces the activation of ERK signaling during the early stages of infection, but only requires ERK for facilitating viral gene transcription, which occurs during later stages of viral infection. Viral genomic replication processes such as: nuclear accumulation of TFs, viral promoter activity, and the transcription of viral early genes and production of viral early proteins, all require MAPK-ERK activity, demonstrating the critical role the MAPK-ERK pathway plays during JCPyV infection. Overall, these works demonstrate that JCPyV, like many DNA viruses, utilizes the MAPK-ERK pathway to dysregulate the host-cell and promote infection. As protein kinases are a new and emerging population of drug targets, characterizing how JCPyV manipulates the MAPK-ERK pathway may identify potential anti-viral therapeutics. Together, these findings have defined how JCPyV activation of the MAPK-ERK cascade specifically upregulates downstream effectors to promote viral infection.

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