Marek's disease (MD) is one of the most economically significant diseases in chickens. It is caused by a highly oncogenic, alpha-herpesvirus named Marek's disease virus (MDV). Currently, the main strategy to control MD is vaccination. However, accumulating evidence points to increase in virulence among MDV field isolates over time, which implicates that new strains of the virus are evolving and could break vaccine protection. This necessitates better understanding of MDV-host interactions, not only to elucidate the events in pathogenesis but also develop strategies for newer and more effective vaccines. One of the major unanswered questions in this area is the mechanism of tumor formation by MDV. The main objective of this project is to gain a comprehensive understanding of host genes that are transcriptionally regulated by Meq, the major oncoprotein of MDV and their relevance in genetic resistance to MD. MDV oncogenicity is largely attributed to the bZIP transcription factor Meq. Although it was discovered in the 1990s, only a few of host target genes have been described. This knowledge gap has impeded our understanding of Meq-induced tumorigenesis. Using a combination of state-of-the-art genomic techniques including ChIP-Seq and microarray analysis, a high confidence list of Meq binding sites and a global transcriptome of genes regulated by Meq was generated. Given the importance of Meq in MDV pathogenesis, we next explored the role of Meq in genetic resistance to MD. Two highly inbred chicken lines, varying in MD resistance, were infected with a virulent strain of MDV, Md5 or a mutant virus lacking Meq, Md-deltaMeq. Analysis of differentially expressed genes provided a list of Meq-dependent genes that are involved in MD resistance and susceptibility. Pathway analysis indicated that MD resistant lines were enriched for positive regulation of cell death whereas the susceptible cell lines were enriched for regulation of cell proliferation. In addition, some of the Meq-regulated pathways like ERK/MAPK signaling and Jak-STAT pathways were also involved in differential MD susceptibility. Taken together, our study provides a comprehensive analysis of how Meq interacts with cellular pathways involved in oncogenesis. In addition, this study forms the basis for selection of candidate genes that might be involved in genetic resistance to Marek's disease.
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