Studentship: Characterisation of molecular targets for differential regulation of the type I interferon induction pathway by rotavirus NSP1

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In recent years it has become increasingly apparent how important the induction of type I interferons (IFN a/ß) in response to the detection of pathogen associated molecular patterns (PAMPs) is in reducing the replication of almost all viruses, before adaptive immune responses are mounted. Most viruses are now known to express an interferon antagonist that reduces type I interferon induction or signalling, resulting in the suppression of an antiviral state which would otherwise reduce virus replication and virulence. Rotaviruses comprise one genus in the Reoviridae family of segmented double stranded RNA viruses. Worldwide, rotaviruses are the major cause of acute viral gastroenteritis in the young of a wide range of mammals including economically important livestock animals and humans. The resulting acute dehydrating diarrhoea and its associated morbidity is a major cause of economic loss to the agricultural industry in livestock animals including cattle and swine. NSP1 is the most variable protein encoded by the group A rotaviruses, unusually for a non-structural protein, and was recently characterised as an interferon antagonist. NSP1 was originally found to be associated with a virulent phenotype in mice in a study of genome segment reassortment between a virulent and non-virulent strain. Recent functional studies have shown that NSP1 reduces the transactivation of the type I interferon genes (IFNa/ß) in infected animals and in cell culture. NSP1 of some strains has been shown to target interferon responsive factor (IRF) 3 for degradation at the proteasome. In contrast, the porcine OSU strain targets another branch of this pathway, the regulator of NK-kappaB, ß-TrCP. It remains unclear whether NSP1 from different host species downregulates the induction of interferon by targeting different host proteins in this signalling pathway or if all NSP1s target a set of proteins which are the common targets irrespective of the host species of origin.

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