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Ubiquitin Signalling Pathways Required for Influenza Virus Replication: Biological Characterisation and Identification of Novel Drug Targets (UBIFLU)
Start date: Aug 1, 2012, End date: Jul 31, 2016 PROJECT  FINISHED 

Influenza viruses are a significant seasonal disease burden, and provide an ever-present threat of causing severe pandemics with potentially devastating clinical, social, and economic consequences. Vaccines and antivirals are available for the prevention and treatment of influenza. However, it often takes too long to manufacture, distribute, and administer an effective strain-matched vaccine under pandemic circumstances, while drug-resistant viruses often emerge against the approved antivirals. Thus, there is urgent need to develop new antivirals with lower chances of selecting drug-resistant strains.Influenza viruses rely extensively on host cell functions, therefore one way to minimise resistance is to target antivirals against host proteins required for virus replication. Here, I will investigate 10 cellular E3 ubiquitin and ubiquitin-like ligases with ‘druggable’ qualities that have been identified in genome-wide siRNA screens as potential host factors required for influenza virus replication. I will confirm their involvement in supporting replication of a broad range of influenza virus strains (including seasonal and pandemic viruses), and attempt to delineate their mechanism of action. By depleting cells of each E3 ligase, and using novel large-scale SILAC- and affinity- based quantitative proteomic techniques, I seek to identify global changes to the cellular ‘ubiquitin-ome’ during virus infection, and correlate these changes with specific host E3 ligases. My work should establish functional and mechanistic links between E3 ligases required for virus replication and the ubiquitin or ubiquitin-like modifications they cause. I hypothesise that there are specific modifications on cellular or viral proteins that are essential for virus replication. Understanding the mechanisms underlying these modifications will provide insights into the interplay between influenza viruses and their hosts, and could represent potential new therapeutic targets.
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