The Macdonald group embraces interdisciplinary research and many of our projects are in collaboration with colleagues in Leeds and around the world. We firmly believe in this research model and the benefits that are acrued by sharing research ideas with colleagues.
We study four major human pathogens in the laboratory.
1. Human papillomavirus (HPV).
2. BK Polyomaviruses (BKPyV).
3. JC Polyomavirus (JCPyV).
4. Merkel Polyomavirus (MCPyV).
Members of the Papillomavirus and Polyomavirus families are the causative agents of a number of severe diseases in humans. HPV is associated with 5% of all human cancers, most notably cervical cancer in women and head and neck squamous cell carcinoma in men and women. Worryingly, HPV infection is also associated with an increased incidence of anal, vaginal and penile cancers. A number of human polyomaviruses are known to cause disease in immunosuppressed patients. In particular polyomavirus-associated nephropathy (PVAN), caused by BKPyV, is a significant cause of kidney transplant rejection and progressive multifocal leukoencephalopathy (PML), caused by JCPyV, is a life threatening demyelinating disease in a sub-set of patients receiving immunosuppressive therapies for chronic conditions including multiple sclerosis. Additionally, the Merkel cell polyomavirus is a causative agent of the highly aggressive skin cancer, Merkel cell carcinoma (MCC), which is increasing in incidence around the world. Current therapeutic strategies to treat these diseases are lacking. We have established a multi-disciplinary research group to undertake a broad ranging analysis of these viruses in the hope that a greater knowledge of their biology may yield new targets for therapeutic intervention.
1. Human papillomaviruses (HPV).
Despite the availability of a vaccine, the incidence of HPV-associated cancer is unlikely to be significantly reduced for decades and the lack of effective pre-existing anti-viral therapeutics highlights the need for a greater understanding of the mechanisms of HPV pathogenesis. We have a major research focus to study the molecular mechanisms HPV utilises to regulate an infected cell. We focus our attention on the least understood of the three transforming proteins encoded by HPV. E5 is a small, membrane protein expressed by all carcinogenic papillomaviruses. Little is known of the role of E5 in the virus life cycle or its mechanisms of pathogenesis. We have made a number of critical breakthroughs in our understanding of this protein. Most notably, we discovered that E5 functions as a virus-encoded ion channel or viroporin (Wetherill et al., 2012). We utilised de novo models of an E5 channel complex (Figure 1A) to identify small molecule inhibitors of E5 channel function and are currently using these models to reveal the functional determinants of E5 channel function in vitro. This work is funded through a three year MRC project grant and employs Dr Emma Prescott and Rajni Bhardwaj. We work closely with Dr Stephen Griffin at St-James University Hospital and Dr Richard Foster in the School of Chemistry on this project. We have also identified novel host binding partners for E5 and are using cell biological approaches to explain their contribution to the HPV life cycle (Muller et al., 2015). We are also one of the few laboratories in the UK to have established three dimensional primary cell culture models to propagate HPV in culture. These "raft cultures" faithfully recapitulate keratinocyte differentiation to allow a detailed analysis of the entire HPV life cycle (Fig 1B). We are using this system to elucidate the function of E5 in the HPV life cycle. Our data reveals that E5 may play a more substantial role in HPV replication than originally realised. These studies are a close colaboration with Dr Sally Roberts at the University of Birmingham. Our multi-faceted approach allows us to make great progress in uncovering the mysteries of E5 and we are now recognised as s a leading laboratory worldwide for the study of E5
2. Human Polyomaviruses (PyVs).
Our research currently covers three major polyomaviruses associated with disease in humans. These are the Merkel, JC and BK polyomaviruses. We combine biochemical, cell biological and virological techniques to further our understanding of their life cycles and mechanisms of pathogenesis.
Merkel Polyomavirus (MCPyV).
Merkel cell carcinoma (MCC) is a highly aggressive human cancer of the
skin that occurs in elderly and immunosuppressed patients. Merkel cell
polyomavirus was discovered in 2008 and is present in 80% of human
Merkel cell carcinomas. Therefore, MCPyV is likely to have a causative
role in MCC. Due to its recent discovery, little is known about the link
between MCPyV and MCC (Stakaitytė et al., 2014). In collaboration with Prof. Adrian Whitehouse (University of Leeds), we have used a quantitative proteomics approach to identify interactions between the transforming proteins of this virus and host cells. We have made a number of discoveries, in particular we have dissected the role of the small T antigen (ST) in immune evasion and metastasis (Griffiths et al., 2013)(Knight et al., 2014).
BK and JC Polyomaviruses (BKPyV/JCPyV).
We have recently established systems in the laboratory to study the entire BK and JC virus life cycles in physiologically relevant cells. We are now using these to understand in unprecedented detail the distinctive stages of virus infection and to identify host and virus proteins that contribute to infection and pathogenesis. In particular, we are once more focussing our attention on the least understood virus encoded proteins, which includes the agnoproteins and minor capsid proteins. We have recently identified novel host factors essential for infection and using a structural approach, in collaboration with Dr Neil Ranson (University of Leeds), we have generated the highest resolution structure of a human polyomavirus using electron microscopy. Using a structural approach, in conjunction with our knowledge of the host pathways, we are now in an ideal position to identify novel compounds to inhibit BK/JC infection. This medicinal chemistry approach is in collaboration with Dr Richard Foster in the School of Chemistry.
Research is funded by a variety of sources including the Medical Research Council (MRC), Cancer Research UK (CRUK), Kidney Research UK (KRUK), the Wellcome Trust and Yorkshire Kidney Research Fund (YKRF).