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Investigations into Differences between Vaccinia and Myxoma Virus Plaquing Properties Identifies Strategies for Increasing the Oncolytic Efficacy of Myxoma Virus Open Access


Other title
Increasing the Oncolytic Efficacy of Myxoma Virus through Enhanced Viral Spread
Viral spread
xenograft tumor model
in vivo imaging
Myxoma Virus
Vaccinia Virus
Oncolytic virus
Type of item
Degree grantor
University of Alberta
Author or creator
Irwin, Chad Robert
Supervisor and department
Evans, David (Medical Microbiology and Immunology)
Examining committee member and department
Connor, John (Boston University School of Medicine)
Smiley, James (Medical Microbiology and Immunology)
Wozniak, Richard (Cell Biology)
Shmulevitz, Maya (Medical Microbiology and Immunology)
Department of Medical Microbiology and Immunology
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Despite both being poxviruses, vaccinia (VACV) and myxoma (MYXV) form very different plaque types. VACV plaques are large and show a central clearing of cells, while MYXV plaques are smaller and result in a clumping of cells. VACV spread is promoted by the formation of an enveloped form of virus (EV) and localized actin rearrangements (called actin tails), which push EV from a cell. Since mutations in genes that catalyze these processes often reduce VACV plaque size (i.e. mutants are more MYXV-like), we investigated the relative efficiency of these viruses to produce actin tails. MYXV forms far fewer actin tails than VACV. Bioinformatics identified MYXV counterparts to these VACV genes - minus one. MYXV lacks a F11 homolog. F11 promotes VACV spread by disrupting cortical actin through inhibition of RhoA-mDia1 signaling. We hypothesized the absence of a MYXV F11 homolog explains these plaquing differences and therefore generated a recombinant MYXV that expresses F11. This virus formed larger plaques, grew to higher levels, and induced a number of cellular morphological changes not observed in control MYXV strains. These included cell rounding, disruption of cortical actin, and more actin tails. F11+ MYXV formed smaller plaques and less actin tails than VACV, suggesting that while an absence of F11 partially explains why MYXV forms smaller plaques than VACV other differences likely exist. MYXV naturally has oncolytic abilities, but does not spread well outside of lagomorphs, which could limit its abilities to treat cancer. We thought that enhanced spread conferred by F11 might increase MYXV’s oncolytic effectiveness. F11+ MYXV showed enhanced abilities to control tumor growth and prolong survival in xenografted mice bearing human mammary tumors. This virus also spread more efficiently from an injected tumor, to a second untreated tumor. We could mimic F11’s stimulatory effects on MYXV growth in cell culture by pharmacological inhibition or siRNA-mediated silencing of key regulators of the actin cytoskeleton. This suggests that chemical disruption of actin could enhance wildtype MYXV’s oncolytic capacity. Since all viruses must overcome barriers to exit, like cortical actin, this approach could be used to improve the effectiveness of other oncolytic viruses.
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
C.R. Irwin and D.H. Evans. Modulation of the myxoma virus plaque phenotype by vaccinia virus F11 protein. J Virol . 2012. 86(13): 7167-79

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