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Abstract
Norovirus (NoV) is one of the most common human pathogens that causes acute gastroenteritis globally. NoVs which belong to a single genotype (of more than 36) namely the Genogroup II, genotype 4 (GII.4), are of particularly importance because they are responsible for ~70% of all NoV infections globally. The emergence of a novel NoV GII.4 variant occurs every two to three years and leads to an increase in gastroenteritis cases and outbreaks. Hence it is important to continuously monitor the circulation of NoV strains. The first aim of this thesis was to study the molecular epidemiology of NoV in the Asia Pacific region including; Singapore, Australia and New Zealand. In this study, three comprehensive molecular epidemiological studies were performed to characterise NoV strains circulating in Singapore (2004 – 2011), Australia (2010 – 2014) and New Zealand (2013 – 2014). GII.4 viruses were the most predominant NoVs identified in all three regions (54.7 – 80.8%) during the study period. A novel GII.4 pandemic variant, Sydney 2012 was also first identified in early 2012. Generally the temporal dominance of GII.4 variants identified in this study coincided with global pandemics of gastroenteritis. Also, recombination was commonly detected in NoVs from this study cohort which could classify viruses into 21 distinct recombinant types. The mitigation or infection control of NoV is difficult due to the lack of effective vaccine or antiviral. This is partly due to limitations in propagating human NoV in cell culture, which has hampered the study of NoV biology, antiviral development and pathogenesis. Another aim of this thesis was to understand how MNV infection avoids the host innate immune response using murine NoV (MNV) as a surrogate model of human NoV. Work in this thesis provides evidence that NoV employs strategies to regulate type-I IFN signalling pathways by inhibiting IRF3 activation by phosphorylation. This thesis also aimed to use the MNV cell culture model to assess the inhibitory effect of four recently identified non-nucleoside inhibitors. The compounds represent early stage, first-in-class antiviral compounds directly targeting the viral polymerase. Results showed each compound had low micromolar inhibitory activity against NoV in this system. The compounds provide a starting framework for the development of NoV targeted antivirals. Overall this thesis has provided insights into the molecular epidemiology of NoV in Singapore, Australia and New Zealand, host-virus interactions pertaining to the innate immune response and assessed the efficacy of direct-acting antiviral agents against NoV.