Use this URL to cite or link to this record in EThOS:
Title: Elucidating early events in the lifecycle of Merkel cell polyomavirus
Author: Dobson, Samuel John
ISNI:       0000 0004 8501 0733
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2019
Availability of Full Text:
Access from EThOS:
Access from Institution:
The Polyomaviridae are a family of viruses which have several lifecycle requirements that have been poorly studied. However, association of these viruses with disease in an immunocompromised host has been well documented. The 2008 discovery of Merkel cell polyomavirus (MCPyV) as the causative agent in Merkel cell carcinoma (MCC) represented the first link of polyomavirus infection to cancer in humans. Further research identified the requirements of a truncation in the large tumour antigen (LT) and clonal integration of mutated viral genomes into the host genome. Despite truncation of LT being essential to MCPyV-positive MCC, the small tumour antigen (ST) has been implicated as the major oncogene that transforms the host cell and promotes several phenotypes associated with cancer. Previous publications in the Whitehouse laboratory have identified the requirement of ST in stimulating events that contribute to the highly metastatic nature of virus induced MCC. ST facilitates microtubule destabilisation and filamentation of actin to prime the cellular cytoskeleton for movement, however despite identifying the essential interaction with the protein phosphatase 4 catalytic subunit (PP4C), the molecular mechanisms through which these changes are brought about have not been fully investigated. In Chapter 5, we describe how ST activates the p38 mitogenactivated protein kinase (MAPK) in a manner that is dependent upon PP4C perturbation. Using chemical inhibitors, the activity of p38 is shown to be essential to the ability of ST to induce migratory phenotypes both in naïve cells and MCPyVpositive MCC cell lines. Therefore, we provide evidence of cellular mechanisms dysregulated by MCPyV ST to promote metastatic phenotypes, which may provide novel therapeutic targets to restrict MCC spread and improve patient prognoses. Intriguingly, MCPyV expresses only one minor capsid protein (VP) that is incorporated into the capsid, whilst the majority of polyomaviruses encode VP2 and VP3 which are both packaged. Early events in the polyomavirus lifecycle are poorly understood in part due to lack of suitable systems. In Chapter 3, we therefore produced new reporter systems, using MCPyV pseudoviruses to study events during entry and trafficking, and in Chapter 4 focus upon the role of ion channels. Comparison with the prototypic SV40 reveals novel requirements of transient-type Ca2+ and K+ channels for MCPyV and a conserved broad Ca2+ channel dependency for both species. This study highlights clinically available drugs that could potentially be repurposed to restrict diseases that are associated with persistent polyomavirus infections.
Supervisor: Whitehouse, Adrian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available