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Antagonism of Cellular Antiviral Systems by Flaviviruses Open Access


Other title
stress granules
antiviral system
Zika virus
Type of item
Degree grantor
University of Alberta
Author or creator
Hou, Shangmei
Supervisor and department
Hobman, Tom (Cell biology)
Examining committee member and department
Hobman, Tom (Cell biology)
Rachubinski, Richard (Cell biology)
Marchant, David (Medical microbiology and immunology)
Banfield, Bruce (Biomedical and molecular sciences)
Schang, Luis M. (Biochemistry)
Department of Cell Biology

Date accepted
Graduation date
2017-11:Fall 2017
Doctor of Philosophy
Degree level
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.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. 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.
Citation for previous publication
You, J., Hou, S., Malik-Soni, N., Xu, Z., Kumar, A., Rachubinski, R.A., Frappier, L., Hobman, T.C. (2015) Flavivirus Infection Impairs Peroxisome Biogenesis and Early Antiviral Signaling. J Virol. 2015 Dec;89(24):12349-61. doi: 10.1128/JVI.01365-15.Kumar, A., Hou, S., Airo, A.M., Limonta, D., Mancinelli, V., Branton, W., Power, C., Hobman, T.C. 2016. Zika virus inhibits Type- I interferon production and downstream signaling. EMBO Rep 17:1766–1775.Hou, S., Kumar, A., Xu, Z., Airo, A.M., Stryapunina, I., Wong, C. P., Branton, W., Tchesnokov, E., Gӧtte, M., Power, C., Hobman, T.C. 2017. Zika virus hijacks stress granule proteins and modulates the host stress response. J Virol. doi:10.1128/JVI.00474-17.

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