Characterisation of the evolutionary history and molecular biology of Louping ill virus

Clark, Jordan John (2018) Characterisation of the evolutionary history and molecular biology of Louping ill virus. PhD thesis, University of Glasgow.

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Louping ill virus (LIV; Flavivirus, Flaviviridae) is a poorly characterised animal pathogen of significant economic concern within the UK. Transmitted by ticks, LIV predominantly causes disease in ruminants and grouse, resulting in substantial losses. LIV is closely related to another Flavivirus, tick-borne encephalitis virus (TBEV), a significant human pathogen. Conversely, human cases of LIV are rarely reported and it is not considered a human pathogen. The phylogenetic relationship between LIV and TBEV is unclear and the molecular mechanisms that underpin host restriction in these viruses are poorly understood. The work presented in this thesis describes the characterisation of LIV using both phylogenetic and molecular approaches. Phylogenetic analysis, utilising a dataset of over 22 LIV genomes sampled over 84 years, indicates that LIV has spread throughout the UK predominantly by localised transmission events. However, several long-distance dispersal events are evident, indicating that LIV spread has likely been exacerbated by human processes such as livestock movement. Despite the LIV dataset spanning almost a century, a molecular clock signal could not be reliably estimated. This raises doubts about the clock rates which have been estimated for other closely related tick-borne flaviviruses. Previously it has been shown that the TBEV non-structural (NS) proteins do not act as type-I interferon (IFN) antagonists, quite unlike other Flavivirus NS proteins. Therefore, to facilitate comparison between LIV and TBEV, the possible antagonistic actions of the LIV NS proteins was investigated. Several LIV NS proteins were identified which function as antagonists throughout the IFN induction cascade. Additionally, the structure of the LIV subgenomic flavivirus RNA (sfRNA) was modelled and compared to TBEV, and it was found that both exert antagonistic effects within the IFN induction pathway. Finally, herein is described the development of the first LIV reverse genetics system based on circular polymerase extension reaction (CPER). This powerful tool can be used in the future to produce chimeric viruses which would allow further investigation into the factors governing host restriction and virulence in tick-borne flaviviruses. In summary, the results described within this thesis provides insight into the evolution of LIV and elucidates the immune evasion strategies employed by LIV during infection. Additionally, the outputs of this thesis provide important tools to further investigate the mechanisms governing host restriction and virulence within the tick-borne flavivirus sub-complex.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: PhD carried out in collaboration with the Moredun Research Institute. Material used during PhD for research was provided by Moredun.
Keywords: Louping ill, virology, evolution, reverse genetics, interferon, flavivirus.
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QR Microbiology > QR180 Immunology
Q Science > QR Microbiology > QR355 Virology
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Supervisor's Name: Kohl, Professor Alain F. and Biek, Dr. Roman and McInnes, Dr. Colin
Date of Award: 2018
Embargo Date: 25 April 2021
Depositing User: Dr Jordan J. Clark
Unique ID: glathesis:2018-38982
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 25 Apr 2019 10:22
Last Modified: 01 Aug 2022 08:42

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