... understanding life in molecular detail

Dr Andrew Macdonald

Virus, Chronic disease, Host interactions, Therapeutics, Cancer


Our research is focussed on understanding the biology of small DNA tumour viruses from the Papillomavirus and Polyomavirus families. These viruses are the cause of significant global morbidity and mortality and are associated with chronic, life long infections in vast swathes of the population. We use an interdisciplinary approach encompassing virology, cell biology with protein biochemistry and structural biology in order to define the interactions with the host necessary for virus infection and pathogenesis.

Current major projects include:
  • Validating host and virus encoded ion channels as targets for therapy
  • Identifying host factors essential for DNA tumour virus replication
  • Virus immune evasion
  • Mechanisms of virus-induced transformation

DNA Tumour Virology

Our multidisciplinary research team studies members of the Papillomavirus and Polyomavirus families. Our research aims to elucidate the mechanisms by which these viruses persist in a healthy host and the host factors necessary for causing disease. Ultimately we wish to identify targets for therapeutic intervention.

 

1. Human papillomaviruses (HPV).

High-risk HPVs are the causative agents of cervical cancer, which is diagnosed in 500,000 women each year and results in 275,000 deaths annually. In addition, they are associated with a growing number of mucosal malignancies affecting both men and women, including anal cancer, vaginal and penile cancer and head and neck squamous cell carcinoma (HNSCC). 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.

 

1.1 Characterisation of novel host factors required for virus replication and disease

Utilising antibody array technologies, we have identified a number of host factors necessary for the HPV life cycle and cancer cell proliferation and survival. We are using cell biology and biochemical approaches to understand the molecular basis for their role in the virus life cycle and are testing small molecule inhibitors as possible therapeutics.

 

1.2 Studying the role of the E5 oncoprotein in the HPV life cycle and in disease

We have focussed our analysis on the least understood of the three transforming proteins encoded by this virus. The E5 protein is a small, membrane protein expressed by all carcinogenic papillomaviruses. Little is understood of the role of E5 in the virus life cycle or its mechanisms of pathogenesis. We recently 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 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. 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 are complimenting our in vitro experiments with a detailed analysis of the role of E5 in the HPV life cycle. For this we have generated HPV genomes containing a stop-codon in the E5 sequence, which effectively creates an E5 knockout virus. Dr Chris Wasson is spearheading these studies and has shown that E5 plays a critical role in deregulating the keratinocyte cell cycle and manipulates the differentiation programme of the epithelium. These studies are a close collaboration with Dr Sally Roberts at the University of Birmingham.

A key to understanding how virus proteins subvert normal cellular processes is to identify the cohort of cellular binding proteins for your virus protein of interest. We have been working on the characterisation of novel E5 binding partners using a global proteomic analysis. We are assessing the roles of the novel binding partners in the HPV life cycle and in pathogenesis.

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.

2.1 Merkel Polyomavirus (MPv).

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. In collaboration with Prof. Adrian Whitehouse (University of Leeds), we are currently investigating the interactions between the transforming proteins of this virus and host cells.

2.2 BK and JC Polyomaviruses (BKPyV/JCPyV).

We are undertaking a joint structural and biochemical analysis of these viruses. In collaboration with Prof. Neil Ranson at Leeds we solved the highest resolution structure of a native BK virus using cryo-electron microscopy (Hurdiss et al., 2016). Follow up work is aimed at understanding the molecular composition of the virion and identifying the role of the minor capsid proteins in virion assembly and genome packaging. We are also keen to understand how structural changes in the capsid mediate virus infection.

 

In addition to these structural studies we have established systems in the laboratory to study the entire polyomavirus life cycle. We are using these systems to interrogate the roles of less understood virus proteins including the minor capsid proteins and the enigmatic agnoproteins. These are small, membrane proteins that are expressed later in the virus infection and may be necessary for production of infectious virus. We have generated recombinant agnoproteins and our preliminary biochemical tests suggest that they are ideal targets for antiviral therapeutics. Work funded by Yorkshire Kidney Research Fund and Kidney Research UK will continue to determine their role in the virus life cycle and also refine potential small molecule inhibitors to prevent their function in cells. This work is in collaboration with Dr Richard Foster in the School of Chemistry.

Detailed research programme                  Close ▲
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Associate Professor
BSc (Leeds) PhD (Leeds)
Promega and Society for General Microbiology Young Microbiologist of the Year

Post-Doc (Leeds) 2002-2004
MRC Career Development Fellow, (MRC Protein Phosphorylation Unit, Dund
RCUK Academic Fellow (Leeds) 2006-2011
Lecturer (Leeds) 2011-2013

Garstang 8.53e
School of Molecular and Cellular Biology
0113 343 3053
a.macdonald@leeds.ac.uk

http://www.fbs.leeds.ac.uk/staff/Macdonald_A/

Selected Publications

  1. Hurdiss, Morgan, Thompson, Prescott, Panou, Macdonald* & Ranson* (2016).  New Structural Insights into the Genome and Minor Capsid Proteins of BK Polyomavirus using Cryo-Electron Microscopy. Structure. 5;24(4):528-36.

    Front cover article and topic of Preview article; Buck. (2016). Exposing the molecular machinery of BK polyomavirus. Structure. 5:24(4):495.

  2. Richards, Wasson, Watherston, Doble, Blair, Wittmann & Macdonald (2015).  Human papillomavirus (HPV) E7 protein antagonises a novel imiquimod-induced inflammatory pathway in primary keratinocytes. Scientific Reports. 13;5: 12922.

  3. Muller, Wasson, Bhatia, Boxall, Millan, Goh, Haas, Stonehouse & Macdonald (2015).  YIP1 family member 4 (YIPF4) is a novel cellular binding partner of the papillomavirus E5 proteins. Scientific Reports. 3;5:12523.

  4. Wetherill, Holmes, Verow, Muller, Howell, Harris, Fishwick, Stonehouse, Foster, Blair, Griffin and Macdonald (2012). High-risk human papillomavirus E5 oncoprotein displays channel forming activity sensitive to small molecule inhibitors. J. Virol 86(9): 5341-51