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Antagonism of Cellular Antiviral Systems by Flaviviruses

  • Author / Creator
    Hou, Shangmei
  • Flaviviruses are important human pathogens that have an enormous impact on global health. Examples that have been studied in my research include dengue virus (DENV), West Nile virus (WNV) and most recently, Zika virus (ZIKV). Currently, there are very few vaccines against or therapeutic treatments for flavivirus infections, and our understanding of how these viruses causes diseases is rather limited. Accumulating evidence from our laboratory and others has demonstrated that flaviviruses target specific host cell proteins to counteract the innate immune systems during infection. In this thesis, I investigated the mechanisms by which DENV, WNV and ZIKV interfere with cellular antiviral pathways, including the peroxisome-mediated antiviral response, the Type-I interferon response, and the host stress response. A major finding was that flavivirus infection impairs biogenesis of peroxisomes, organelles that are important signaling platforms for early antiviral response including interferon production. This phenomenon is due in part to sequestration of the essential peroxisome biogenesis factor PEX19 by the viral capsid proteins. Analyses of ZIKV-infected cells revealed that this emerging pathogen interferes with the interferon production and signaling through multiple mechanisms. Specifically, the viral non-structural proteins NS1, NS4A and NS5 were identified as suppressors of interferon induction. NS5 was shown to target the antiviral transcription factor STAT2 for proteasomal degradation. Lastly, ZIKV infection was shown to modulate the cellular stress response and inhibit stress granule formation. The virus utilizes multiple viral components to hijack key stress granule proteins likely to facilitate viral replication. Together, this thesis work describes novel host-virus interactions that occur during flavivirus infection and provides mechanistic insights into these processes, which in turn may provide new avenues for therapeutic development.

  • Subjects / Keywords
  • Graduation date
    2017-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R35H7C73C
  • 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
    • Department of Cell Biology
  • Supervisor / co-supervisor and their department(s)
    • Hobman, Tom (Cell biology)
  • Examining committee members and their departments
    • Rachubinski, Richard (Cell biology)
    • Marchant, David (Medical microbiology and immunology)
    • Hobman, Tom (Cell biology)
    • Schang, Luis M. (Biochemistry)
    • Banfield, Bruce (Biomedical and molecular sciences)