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Functional Analyses of West Nile virus-Host Interactions

  • Author / Creator
    Xu, Zaikun
  • West Nile virus (WNV) is a neurotropic, blood-borne flavivirus that can
    cause serious neurological disease in humans and animals. While significant
    progress has been made in identifying virus-encoded pathogenic determinants,
    very little is known regarding how these viral proteins interact with host cell
    proteins. Recent evidence suggests that in addition to its structural role in
    packaging genomic RNA, the WNV capsid protein plays important roles in virus
    host interactions and therefore, characterizing the interactions between capsid and
    cellular proteins should contribute to our understanding of WNV disease and may
    even reveal targets for antiviral therapy. Through an extensive yeast two-hybrid
    screen, I identified DDX56, a novel WNV capsid-interacting nucleolar RNA
    helicase. Experimental analyses revealed DDX56 is not required for production of
    viral RNA or proteins, however, WNV virions secreted from DDX56-depleted
    cells are 100 times less infectious than those produced in normal cells.
    Collectively, these data suggest that DDX56 is critical for assembly of infectious
    WNV virions possibly by facilitating the packaging of viral RNA.
    I also investigated how WNV infection affects tight junctions in polarized
    cells with the goal of understanding how the virus breaches the blood-brain
    barrier to gain access to the central nervous system. While a number of recent
    studies have documented that WNV infection negatively impacts the barrier
    function of tight junctions, the intracellular mechanism by which this occurs is
    poorly understood. Using a coordinated approach to understand the direct effects
    of WNV infection on tight junction proteins in both epithelial and endothelial
    cells, I discovered that WNV infection results in endocytosis of a specific subset
    of tight junction membrane proteins including claudin-1 and JAM-1 followed by
    microtubule-based transport to and degradation in lysosomes. Further studies into
    this process could lead to therapeutic treatments that block viral spread and/or
    design of attenuated vaccine strains.

  • Subjects / Keywords
  • Graduation date
    Fall 2013
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3V11VS6W
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Wozniak, Richard (Cell Biology)
    • Russell, Rodney (BioMedical Sciences)
    • Smiley, Jim (Medical Microbiology & Immunology)
    • Marchant, David (Medical Microbiology & Immunology)