Intrinsic Immunity

Dr Chris Boutell, Lead Investigator, MRC-University of Glasgow Centre for Virus Research (CVR), University of Glasgow
The modification of proteins regulates many important aspects of cell biology, including host immunity to infection. Viruses have therefore evolved strategies to utilise or suppress pathways that regulate protein modification to overcome host defences to infection, thereby enhancing their replication, spread, and disease burden. However, these key interactions remain largely undefined at a biochemical level. Work within this programme focuses on two pathways, namely ubiquitin and SUMO (Small Ubiquitin-like MOdifier), which we and others have shown to play an important role in the regulation of host immunity. Our aim is to define the activity of core enzymes that influence the outcome of infection, using herpes simplex virus 1 (HSV-1) as a model DNA virus. These studies will reveal unique insight into the mechanisms that regulate host immunity during DNA virus infection, as well as uncovering fundamental principles that regulate other important areas of cell biology relevant to human disease, for example carcinogenesis. By understanding these principles we aim to develop new targeted approaches for future therapeutic intervention to treat viral infections pertinent to public health.

The post-translational modification (PTM) of proteins by ubiquitin and ubiquitin-like (UBL) polypeptides regulates many fundamental aspects of cell biology, including multiple facets relating to host immunity. Viruses have therefore evolved mechanisms to utilise or suppress these PTM pathways to overcome host immune defence mechanisms during infection, thereby promoting their replication and spread. Understanding the biochemical interplay between viral and host factors which utilise these pathways will therefore lead to new insights into the regulation of host immunity, processes which restrict the replication of many clinically important viruses. This programme aims to define the biochemistry of key viral host-cell interactions that utilise ubiquitin and SUMO PTM pathways to influence the outcome of host immunity during herpesvirus infection, using HSV-1 as a model system. By defining the biochemistry of these interactions we aim to: significantly advance our understanding of the signalling mechanisms that mediate the cellular restriction of herpesviruses and the establishment of viral latency; uncover fundamental principles relating to the regulation of ubiquitin and SUMO ligases that mediate key aspects of cellular immunity during HSV-1 infection; develop methodologies suitable for the identification of viral ubiquitin ligase inhibitors using ICP0 as a model ligase.
This programme will add significant value to the MRC, CVR, and its associated research partners through the delivery of an interdisciplinary and internationally competitive programme of research. This programme will strengthen the study of ubiquitin and ubiquitin-related pathways within the CVR in other virus systems, including influenza A virus (IAV), Hepatitis C Virus (HCV), and selected arboviruses, through the dissemination of research reagents and expert knowledge. Our goal is to define the functional significance and host-cell regulation of these important PTM pathways during infection, thereby revealing fundamental insight into the biochemical mechanisms that influence the outcome of viral infection and pathogenesis