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Permanent link (DOI): https://doi.org/10.7939/R36M4F

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Characterization of the anti-apoptotic properties of flavivirus capsid proteins Open Access

Descriptions

Other title
Subject/Keyword
apoptosis
virus
capsid
PI3K
flavivirus
akt
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Urbanowski, Matthew D.
Supervisor and department
Dr. Tom C. Hobman (Cell Biology)
Examining committee member and department
Dr. David Evans (Medical Microbiology and Immunology)
Dr. Paul Melancon (Cell Biology)
Dr. Karen Mossman (Biochemistry) - McMaster University
Dr. Ing Swie Goping (Biochemistry)
Department
Department of Cell Biology
Specialization

Date accepted
2014-01-08T11:36:41Z
Graduation date
2014-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The introduction of WNV into North America in 1999 was followed by rapid spread throughout the continent. Today, WNV is an endemic pathogen in the west, with thousands of cases of severe infection reported annually. In addition to traditional vaccine research, there is an urgent need to understand the contributions of individual virus components to the infection process. This includes the capsid protein, which has until recent times has been thought only to be a structural protein. As the sole component of the nucleocapsid, the capsid protein serves the essential function of both providing structure to the virion and protecting the viral genome. However, recent research would suggest that in addition to these functions, capsid can serve to modulate the host cell environment to create a more permissive environment for viral replication and spread. Viruses such as WNV that exhibit slower replication kinetics must employ strategies to avoid host responses which attempt to prevent viral replication. One such critical strategy is the prevention of cell death. A growing number of reports in the literature have described mechanisms whereby viral proteins can blunt the apoptotic response to permit efficient virus replication. This can be mediated through enhanced activity of the ubiquitous and highly regulated PI3K/Akt pathway. Indeed, WNV appears to utilize this pathway to prolong cell survival during infection. In my thesis, I describe the anti‐apoptotic properties of WNV and other flavivirus capsids, and demonstrate their ability to suppress apoptosis triggered by ligation of Fas. In concordance with this, I show that those capsids which block apoptosis triggered by anti‐Fas enhance phosphorylation of Akt. The inhibition of this kinase through the use of the inhibitor LY294002 prevents WNV capsid mediated suppression of apoptosis triggered by Fas ligation. In support of this first study, I also demonstrate that capsid proteins are able to promote cellular proliferation, even in the absence of growth factors. Curiously, this phenomenon includes those capsid proteins which do not protect against anti‐Fas. The characterization of these properties of flavivirus capsid proteins provides greater insight into the biology of the viruses they are derived from.
Language
English
DOI
doi:10.7939/R36M4F
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Urbanowski M.D., Hobman T.C. (2013). The West Nile virus capsid protein blocks apoptosis through a phosphatidylinositol 3-kinase-dependent mechanism. J. Virol. 87(2):872-81.

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