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Title: The evolution of GII.4 norovirus and the sources and drivers of norovirus pandemics
Author: Ruis, Christopher
ISNI:       0000 0004 7229 1054
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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The norovirus genotype GII.4 is a leading cause of human gastroenteritis worldwide and has caused six pandemics since the mid-1990s. In this thesis, we use phylogenetic analyses to investigate the evolutionary history of the GII.4 genotype and the sources and drivers of norovirus pandemics. We first examine the early history of GII.4 and suggest that the increased prevalence of GII.4 concomitant with the first pandemic was a `perfect storm' where a virus capable of accommodating a high level of amino acid change with a high mutation rate enabling efficient transmission acquired a highly stable viral capsid and/or an increased susceptible population size by expanding its receptor-binding repertoire. We next reconstruct the temporal history of GII.4 and demonstrate that each pandemic strain circulated undetected within poorly sampled reservoir populations for years prior to pandemic emergence. Over several years prior to pandemic emergence, the strain diversifies into a large number of lineages and spatiotemporal reconstruction suggests the strain undergoes low-level worldwide circulation. This indicates that the viral genetic changes important for pandemic emergence are acquired years prior to the pandemic and are therefore not the proximal driver of pandemic spread; we hypothesise that genetic changes pre-adapt the strain for future emergence by shifting the virus to a new region of antigenic space. We demonstrate significant amino acid diversity within pandemic strains, with highly diverse sites within a strain often coinciding with immune epitopes and/or receptor-binding regions. This diversity begins to be accumulated prior to pandemic emergence. We hypothesise that increasing host population immunity curtails circulation of the preceding pandemic strain and results in a new pandemic by opening a niche into which many closely related but subtly different viral lineages can emerge. Finally, we examine two newly emerging norovirus strains and demonstrate that they share polymerase substitutions that may enable increased transmission.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available