Marek's disease: pathogenic determinants and epigenetic changes

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Marek’s disease (MD) is a major disease of poultry and an excellent model of rapid-onset virus-induced neoplastic disease in chickens. Although MD is currently controlled by the widespread use of live attenuated vaccines, continuing trend in increasing virulence is threatening the efficacy of the currently used vaccines. The overall strategic aim of this WP is to understand the molecular interactions and pathways used by oncogenic viruses in inducing neoplastic transformation to develop more efficient strategies of disease control. As part of this WP we will examine the molecular determinants of MDV associated with oncogenicity in natural infection models, using reverse genetics strategies on infectious BAC clones of MDV that we have developed at IAH. This will include the use of fluorescently tagged viruses and live cell imaging techniques to monitor the viral replication in vitro & in vivo, the use of recombinant viruses to identify the virus-host interaction in tumours of infected birds. In addition, we hope to exploit the various advances in post-genomic technologies to analyse the transcriptome-proteome, miRNA expression and the viral/host protein-protein interactions to take a whole systems approach to identify the molecular pathways of oncogenesis in MD. We also aim to examine the epigenetic changes such as DNA methylation and histone modifications in MD tumour-derived cell lines, as well as laser dissected tumour cells from primary tumours. We believe that these studies will enable better understanding not only on the intricate host-pathogen interactions of oncogenic viruses and molecular pathways of oncogenesis, but also in delivering novel molecularly-defined more effective vaccines. As part of the programme, we will also examine the unique virus-host interactions in the feather follicle of infected cells, the only site where a fully productive infection occurs resulting in the release of the virus into the environment.

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