Investigation into the role of MicroRNAs in pathogenesis of Marek's disease

Marek's disease is one of the most contagious and widespread diseases affecting poultry health and welfare. The causative virus, called Marek's disease virus (MDV) induces a very severe form of cancer of the white blood cells (lymphocytes). Once infected, the virus can persist for the lifetime of the host and is continuously shed from the feather of the infected birds into the environment where it survives for long periods. The mechanisms by which MDV causes cancer is not known. The present project is aimed to identify the mechanisms of causation of the disease by the virus. Recently, several small RNA molecules called microRNAs (miRNAs) have been shown to be involved in different cellular processes including several human cancers. Such small miRNA molecules have been found in the chickens and we have also recently identified several miRNAs in the virus. The present project is aimed to examine whether these small miRNA are involved in the causation of MD.

Marek's disease (MD) is one of the most highly oncogenic herpesviruses known. The causative Marek's disease virus (MDV) is an alphaherpesvirus encoding more than 100 open reading frames. Molecular mechanisms of oncogenesis of MD are not fully understood, although the role of several MDV genes in oncogenesis have been identified. Recently, there has been great interest in the role of non-coding RNAs, particularly the 21-25 nucleotide microRNAs (miRNAs), in various biological processes. In chickens, 122 miRNAs have been identified, although their functional role is not yet clear. Very recently, novel miRNA sequences have also been identified in several herpesviruses. Using new bioinformatic tools, we have identified 9 novel miRNA sequences in the MDV genome, eight of which are clustered in the repeat regiion. This project is aimed to analyse the role of chicken miRNAS and the novel MDV miRNAS by examining their expression profiles and by identifying the potential targets. Finally, using mutagenesis of the bacterial artificial chromosome (BAC) clones of virulent MDV strains, we will examine whether the novel MDV miRNAs are involved in the pathogenesis of MD. The project would provide a fundamental understanding not only on the molecular mechanisms of MDV oncogenicity, but also on the novel methods of gene regulation associated with neoplasia in general.