The Boutell Group
My research aims to define how viruses engage with ubiquitin and ubiquitin-like modification pathways with respect to cellular antiviral immunity, at both the molecular and biochemical level, to develop novel avenues for future therapeutic intervention.
Current work within the laboratory focuses on two modification pathways, namely ubiquitin and SUMO (Small Ubiquitin-like MOdifier), which have been shown to play important roles in the activation and regulation of various aspects of intracellular immunity during virus infection. We study this virus host-cell interface using a number of clinically important viruses, including herpes simplex virus type-1 (HSV-1), hepatitis C virus (HCV), and influenza virus.
Herpes simplex virus 1
HSV-1 is a DNA virus that establishes a life-long latent infection within sensory neurones. Like all herpesviruses, HSV-1 can periodically reactivate causing new episodes of disease. Whilst in most cases this is not serious, reactivation in immuno-compromised individuals can be severe and even life threatening. Since latent virus is neither accessible to the immune system nor current anti-viral treatments, an understanding of the mechanisms that regulate latency is important for future drug development.
One of the first viral proteins to be expressed during infection is ICP0, a viral ubiquitin ligase that targets cellular proteins for degradation. This activity inhibits antiviral defence mechanisms activated in response to infection, thereby allowing the virus to replicate and reactivate from latency efficiently. Understanding how ICP0 interacts with components of the ubiquitin pathway will provide valuable insight into the mechanisms that regulate antiviral immunity in response to herpesvirus infections in general and potentially the development of novel therapeutic strategies for intervention.
Hepatitis C virus
HCV is a small RNA virus that replicates within the liver. Chronic HCV infection is one of the leading causes of non-alcohol related liver disease that can lead to liver cirrhosis and cancer. In collaboration with Dr John McLauchlan within the CVR, our research has shown that HCV significantly up-regulates components of the ubiquitin pathway during infection. Current research aims to establish how HCV engages with the ubiquitin pathway in order to develop a programme of work that could be utilised for future drug development.
Influenza virus is an RNA virus that can cause severe respiratory illness. Due to its segmented RNA genome and high mutation rate, seasonal strains of influenza virus result in a significant health burden to the UK population every year. Little is known about how influenza virus engages with ubiquitin and ubiquitin-like modification pathways during infection.
In collaboration with Dr Ben Hale at the University of Zürich, our research aims to identify and characterise the biological activity of novel host-cell restriction factors that utilise these pathways to suppress virus replication. By identifying these naturally occurring restriction factors, and associated viral counter measures, this programme of work aims to develop novel avenues of research for future therapeutic development.
Internal and external collaborators/stakeholders