RESEARCH

Interest #1: Alteration of the host cell’s transcriptome and epigenome by viral transcriptional regulators.

Viral oncoproteins often alter, on a global scale, the transcriptional programs of infected cells. Work that I have done with adenovirus E1A has shown me that there exists an unappreciated complexity to these interactions. My current research concerns the manner in which these viral proteins alter the transcriptional program of cells.

In particular, I am focusing on how these small DNA tumour virus oncogenes alter transcription of non-coding transcripts (microRNAs) and the state of cellular epigenome. My work, as well as the work of many others with adenovirus E1A has shown that E1A is capable of dramatically altering the transcriptional program of cells. However, the study of non-coding transcripts has largely been ignored.

With the advent of new technologies, in particular DNA chips with non-coding transcripts and microRNAs and novel sequencing techniques (such as RNA-seq), it has now become feasible to do such studies. This work will lead to discoveries of novel pathways and regulators that are involved in viral replication and many other cellular processes, such as regulation of the cell cycle and differentiation.

Additionally, it has the potential to lead to the discovery of novel epigenetic processes critical to regulation of microRNA expression as well as general transcriptional regulation, both in controlling cell state and viral life cycle.

Interest #2: Mechanisms of host immune evasion by highly pathogenic adenoviruses.

Our recent work has shown that the highly pathogenic strains of human adenovirus are much more efficient at replication and evasion of the host immune response. Studies in my lab have shown that these viruses are much more efficient at suppressing activation of the innate defence mechanisms. These include lack of activation of interferon stimulated genes (ISGs) during infection of cells with these viruses, but also highly efficient suppression of ISGs activated by prior treatment of cells with interferon. This potent ability to evade this crucial defence mechanism may be one of the contributing factors to their high virulence, morbidity, and mortality.

We are investigating the role of E1A in innate immunity evasion and the role of other early regions, particularly E3 and E4 in suppression of ISGs and inactivation of the innate immune pathways. By studying these mechanisms, we hope to learn about mechanisms of viral suppression of innate immunity broadly applicable to new and emerging diseases.

Interest #3: The role of Nek9 and other NimA-related kinases during viral infection.

The NimA-family of serine/threonine kinases is a relatively poorly understood subset of protein kinases that appear to play a role in a variety of cellular processes and are targeted by DNA tumour virus proteins such as adenovirus E1A. In particular, the functions of the more recently discovered members of this family are largely unknown.

The NimA-family of kinases play crucial roles in cellular differentiation and cell cycle regulation, processes that are often de-regulated by viruses during infection. Preliminary data generated during my post-doctoral and PhD studies show that Nek9 is critical for differentiation and maintenance of the differentiated state, and as such is an important target for viral oncoproteins.

I am further pursuing these studies in order to identify the roles these kinases play during viral infection and why they are targeted by viral early proteins. In particular I am focusing on their importance in regulating the cell cycle, mitosis and differentiation during infection with adenovirus and HPV.

Due to their role in critical cellular processes regulating growth and differentiation, the NimA-family of kinases represent very attractive therapeutic targets in cancer and further understanding of their function may enable potential therapeutic agents to be developed.