Unravelling the networks that determine and control norovirus infection and pathogenesis. (360G-Wellcome-097997_B_11_Z)

We aim to understand the mechanistic basis for why GII.4 noroviruses have dominated for the past 15 years as well as identifying new mechanisms of controlling and preventing norovirus infection. One goal of the project will determine the contribution of the viral RNA polymerase fidelity and activity to norovirus pathogenesis as the enzyme from pandemic noroviruses is more error prone and has higher activity than non-pandemic noroviruses. We will usecutting edge sequencing methods to characteris e norovirus evolution in the human population, identifying possible pandemic signature mutations in the viral RNA polymerase. We will then characterise the effects of these mutationson RNA polymerase activity, virus replication and virus pathogenesis, identifying new vaccine strategies. State of the art quantitative proteomics will be used to determine the effect of the norovirus replication on the host cell and the role of these pathways examined in more detail. We will then identify small mol ecule inhibitors of these pathways and examine if they haveanti-norovirus activity. We will also consider the role of the host cell RNA quality control pathway in the norovirus life cycle as our preliminary data indicates that this pathway provides an attractive therapeutic target.