The role of ubiquitin and ubiquitin-like proteins during viral infection and host-cell immunity

During infection viruses must evade multiple host defence mechanisms in order to establish a productive infection. These include antibody and cell mediated acquired immunity, interferon regulated innate immunity, and intrinsic cellular immunity. In order to counteract these host defences many viruses have evolved strategies to engage with cellular ubiquitin and ubiquitin-like modification pathways to modulate their intracellular environment in favour of viral replication. This programme of research aims to define how specific viruses engage with components of these pathways in order to design and develop alternative therapeutic intervention strategies.
Our research has identified unique aspects relating to cellular immune defence and associated viral counter measures. Our current work aims to determine whether these pathways affect other clinically important human viruses, and to establish a platform of biochemical techniques that will facilitate the screening of compounds to inhibit viral counter measures of these pathways.

The post-translational modification of proteins by ubiquitin and ubiquitin-related polypeptides regulates many essential cellular processes including protein degradation, transcription, DNA repair and host-cell anti-viral immunity. Consequently, many human viruses have evolved strategies to utilise or suppress these modification pathways in order to enhance their replication, thereby maintaining their presence within the human population. Utilising a variety of techniques; library screening, lentiviral expression, RNAi technologies, in vitro biochemistry and mass spectrometry, the aim of this programme is to identify and biochemically define how human viruses engage with components of these pathways during infection with respect to disarming host-cell anti-viral immunity. This work will provide a platform of biochemistry in order to develop novel strategies for future therapeutic intervention. The lab focuses on three clinically important human viruses: Herpes Simplex virus type-1 (HSV-1), Influenza A virus, and Hepatitis C Virus (HCV).

HSV-1 causes a variety of clinically important diseases, including herpes keratitis and encephalitis, and provides an ideal model system for studying multiple aspects of intracellular immunity in response to DNA virus infection. An important regulator of HSV-1 infection is ICP0, a viral ubiquitin ligase that targets a subset of cellular proteins implicated in anti-viral immune defecne for ubiquitination and proteasome-dependent degradation. Our research aims to identify and characterise the cellular regulators associated with nuclear immunity in response to DNA virus infection, both at a molecular and biochemical level, by virtue of identifying ICP0’s cellular substrates and biochemical specificity.

Recent progress in our understanding of the molecular mechanisms associated with the regulation of intrinsic immunity in response to HSV-1 infection are also being investigated in during the nuclear replication of RNA viruses, specifically Influenza A virus, in order to determine the specificity of these host defence mechanisms. Influenza virus infection is the leading causative agent associated with acute viral respiratory illnesses and causes significant annual morbidity and mortality within humans.

HCV infection is a leading cause of non-alcohol related liver disease within the UK, including decompensated cirrhosis and hepatocellular carcinoma. HCV induces the re-distribution of intracellular ubiquitin conjugates during infection, a phenotype that is dependent upon viral RNA replication. However, little is known about how HCV engages with components of the ubiquitin-pathway or the functional importance of these interactions with respect to viral replication. This research aims to identify and characterise the role of ubiquitin and ubiquitin-like modifications during HCV infection and their relationship to anti-viral defence.