Honors & Awards


  • National CIHR Research Training Program in Hepatitis C, Canadian Institute of Health Research (July 2013 - July 2015)
  • Presidents Doctoral Prize of Distinction, University of Alberta (2009-2011)
  • Studentship, Alberta Innovates - Health Solutions (2009-2012)
  • Alexander Graham Bell Scholarship, NSERC (2009-2012)

Professional Education


  • Doctor of Philosophy, University of Alberta (2012)
  • Bachelor of Science, University of Victoria (2003)

Stanford Advisors


Current Research and Scholarly Interests


Using poliovirus as a model system, the Kirkegaard laboratory has developed a method to decrease the risk of drug-resistance during RNA virus antiviral therapy by targeting dominant drug targets. My goal is to identify equivalent dominant drug targets in hepatitis C virus in order to decrease the risk of drug-resistance during hepatitis C virus antiviral therapy.

Lab Affiliations


Graduate and Fellowship Programs


Journal Articles


  • Ectromelia Virus Encodes a Novel Family of F-Box Proteins That Interact with the SCF Complex JOURNAL OF VIROLOGY van Buuren, N., Couturier, B., Xiong, Y., Barry, M. 2008; 82 (20): 9917-9927

    Abstract

    Poxviruses are notorious for encoding multiple proteins that regulate cellular signaling pathways, including the ubiquitin-proteasome system. Bioinformatics indicated that ectromelia virus, the causative agent of lethal mousepox, encoded four proteins, EVM002, EVM005, EVM154, and EVM165, containing putative F-box domains. In contrast to cellular F-box proteins, the ectromelia virus proteins contain C-terminal F-box domains in conjunction with N-terminal ankyrin repeats, a combination that has not been previously reported for cellular proteins. These observations suggested that the ectromelia virus F-box proteins interact with SCF (Skp1, cullin-1, and F-box) ubiquitin ligases. We focused our studies on EVM005, since this protein had only one ortholog in cowpox virus. Using mass spectrometry, we identified cullin-1 as a binding partner for EVM005, and this interaction was confirmed by overexpression of hemagglutinin (HA)-cullin-1. During infection, Flag-EVM005 and HA-cullin-1 colocalized to distinct cellular bodies. Significantly, EVM005 coprecipitated with endogenous Skp1, cullin-1, and Roc1 and associated with conjugated ubiquitin, suggesting that EVM005 interacted with the components of a functional ubiquitin ligase. Interaction of EVM005 with cullin-1 and Skp1 was abolished upon deletion of the F-box, indicating that the F-box played a crucial role in interaction with the SCF complex. Additionally, EVM002 and EVM154 interacted with Skp1 and conjugated ubiquitin, suggesting that ectromelia virus encodes multiple F-box-containing proteins that regulate the SCF complex. Our results indicate that ectromelia virus has evolved multiple proteins that interact with the SCF complex.

    View details for DOI 10.1128/JVI.00953-08

    View details for Web of Science ID 000260109100011

    View details for PubMedID 18684824

  • A Selectable and Excisable Marker System for the Rapid Creation of Recombinant Poxviruses PLOS ONE Rintoul, J. L., Wang, J., Gammon, D. B., van Buuren, N. J., Garson, K., Jardine, K., Barry, M., Evans, D. H., Bell, J. C. 2011; 6 (9)

    Abstract

    Genetic manipulation of poxvirus genomes through attenuation, or insertion of therapeutic genes has led to a number of vector candidates for the treatment of a variety of human diseases. The development of recombinant poxviruses often involves the genomic insertion of a selectable marker for purification and selection purposes. The use of marker genes however inevitably results in a vector that contains unwanted genetic information of no therapeutic value.Here we describe an improved strategy that allows for the creation of marker-free recombinant poxviruses of any species. The Selectable and Excisable Marker (SEM) system incorporates a unique fusion marker gene for the efficient selection of poxvirus recombinants and the Cre/loxP system to facilitate the subsequent removal of the marker. We have defined and characterized this new methodological tool by insertion of a foreign gene into vaccinia virus, with the subsequent removal of the selectable marker. We then analyzed the importance of loxP orientation during Cre recombination, and show that the SEM system can be used to introduce site-specific deletions or inversions into the viral genome. Finally, we demonstrate that the SEM strategy is amenable to other poxviruses, as demonstrated here with the creation of an ectromelia virus recombinant lacking the EVM002 gene.The system described here thus provides a faster, simpler and more efficient means to create clinic-ready recombinant poxviruses for therapeutic gene therapy applications.

    View details for DOI 10.1371/journal.pone.0024643

    View details for Web of Science ID 000294802800080

    View details for PubMedID 21931792

  • Poxvirus Exploitation of the Ubiquitin-Proteasome System VIRUSES-BASEL Barry, M., van Buuren, N., Burles, K., Mottet, K., Wang, Q., Teale, A. 2010; 2 (10): 2356-2380

    Abstract

    Ubiquitination plays a critical role in many cellular processes. A growing number of viruses have evolved strategies to exploit the ubiquitin-proteasome system, including members of the Poxviridae family. Members of the poxvirus family have recently been shown to encode BTB/kelch and ankyrin/F-box proteins that interact with cullin-3 and cullin-1 based ubiquitin ligases, respectively. Multiple members of the poxvirus family also encode ubiquitin ligases with intrinsic activity. This review describes the numerous mechanisms that poxviruses employ to manipulate the ubiquitin-proteasome system.

    View details for DOI 10.3390/v2102356

    View details for Web of Science ID 000284581900010

    View details for PubMedID 21994622

  • Proteomic screening of variola virus reveals a unique NF-kappa B inhibitor that is highly conserved among pathogenic orthopoxviruses PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Mohamed, R. M., Rahman, M. M., Lanchbury, J. S., Shattuck, D., Neff, C., Dufford, M., van Buuren, N., Fagan, K., Barry, M., Smith, S., Damon, I., McFadden, G. 2009; 106 (22): 9045-9050

    Abstract

    Identification of the binary interactions between viral and host proteins has become a valuable tool for investigating viral tropism and pathogenesis. Here, we present the first systematic protein interaction screening of the unique variola virus proteome by using yeast 2-hybrid screening against a variety of human cDNA libraries. Several protein-protein interactions were identified, including an interaction between variola G1R, an ankryin/F-box containing protein, and human nuclear factor kappa-B1 (NF-kappaB1)/p105. This represents the first direct interaction between a pathogen-encoded protein and NF-kappaB1/p105. Orthologs of G1R are present in a variety of pathogenic orthopoxviruses, but not in vaccinia virus, and expression of any one of these viral proteins blocks NF-kappaB signaling in human cells. Thus, proteomic screening of variola virus has the potential to uncover modulators of the human innate antiviral responses.

    View details for DOI 10.1073/pnas.0900452106

    View details for Web of Science ID 000266580500049

    View details for PubMedID 19451633

  • Orthopoxviruses Require a Functional Ubiquitin-Proteasome System for Productive Replication JOURNAL OF VIROLOGY Teale, A., Campbell, S., van Buuren, N., Magee, W. C., Watmough, K., Couturier, B., Shipclark, R., Barry, M. 2009; 83 (5): 2099-2108

    Abstract

    Cellular homeostasis depends on an intricate balance of protein expression and degradation. The ubiquitin-proteasome pathway plays a crucial role in specifically targeting proteins tagged with ubiquitin for destruction. This degradation can be effectively blocked by both chemically synthesized and natural proteasome inhibitors. Poxviruses encode a number of proteins that exploit the ubiquitin-proteasome system, including virally encoded ubiquitin molecules and ubiquitin ligases, as well as BTB/kelch proteins and F-box proteins, which interact with cellular ubiquitin ligases. Here we show that poxvirus infection was dramatically affected by a range of proteasome inhibitors, including MG132, MG115, lactacystin, and bortezomib (Velcade). Confocal microscopy demonstrated that infected cells treated with MG132 or bortezomib lacked viral replication factories within the cytoplasm. This was accompanied by the absence of late gene expression and DNA replication; however, early gene expression occurred unabated. Proteasomal inhibition with MG132 or bortezomib also had dramatic effects on viral titers, severely blocking viral replication and propagation. The effects of MG132 on poxvirus infection were reversible upon washout, resulting in the production of late genes and viral replication factories. Significantly, the addition of an ubiquitin-activating enzyme (E1) inhibitor had a similar affect on late and early protein expression. Together, our data suggests that a functional ubiquitin-proteasome system is required during poxvirus infection.

    View details for DOI 10.1128/JVI.01753-08

    View details for Web of Science ID 000263209900005

    View details for PubMedID 19109393

  • Ectromelia virus BTB/kelch proteins, EVM150 and EVM167, interact with cullin-3-based ubiquitin ligases VIROLOGY Wilton, B. A., Campbell, S., Van Buuren, N., Garneau, R., Furukawa, M., Xiong, Y., Barry, M. 2008; 374 (1): 82-99

    Abstract

    Cellular proteins containing BTB and kelch domains have been shown to function as adapters for the recruitment of substrates to cullin-3-based ubiquitin ligases. Poxviruses are the only family of viruses known to encode multiple BTB/kelch proteins, suggesting that poxviruses may modulate the ubiquitin pathway through interaction with cullin-3. Ectromelia virus encodes four BTB/kelch proteins and one BTB-only protein. Here we demonstrate that two of the ectromelia virus-encoded BTB/kelch proteins, EVM150 and EVM167, interacted with cullin-3. Similar to cellular BTB proteins, the BTB domain of EVM150 and EVM167 was necessary and sufficient for cullin-3 interaction. During infection, EVM150 and EVM167 localized to discrete cytoplasmic regions, which co-localized with cullin-3. Furthermore, EVM150 and EVM167 co-localized and interacted with conjugated ubiquitin, as demonstrated by confocal microscopy and co-immunoprecipitation. Our findings suggest that the ectromelia virus-encoded BTB/kelch proteins, EVM150 and EVM167, interact with cullin-3 potentially functioning to recruit unidentified substrates for ubiquitination.

    View details for DOI 10.1016/j.virol.2007.11.036

    View details for Web of Science ID 000255325100008

    View details for PubMedID 18221766