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Title: Characterization of molecular targets for differential regulation of the type I and III interferon induction and signalling pathways by rotavirus NSP1
Author: Iaconis, G.
ISNI:       0000 0004 7970 3701
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Rotavirus (RV) is the leading cause of severe dehydrating diarrhoea in infants, infecting almost every child by 3-5 years of age and causing approximately 590,000 gastroenteritis-associated deaths world-wide both in developed and developing countries. The virus infects the young of all mammalian species and cross-species infections and zoonosis events have been reported. However, RV is host replication-restricted during heterologous infection for reasons that are not fully understood. Type I and type III interferons (IFNs) constitute the first line of defence against viral infection. Their expression is triggered when specific viral components (Pathogen-Associated Molecular Patterns - PAMPs), such as dsRNA, are detected within the cells by specific host proteins, Pattern Recognition Receptors (PRR). Once secreted, IFNs bind their specific receptors inducing the expression of interferon stimulated genes (ISGs), establishing an antiviral state. RV non-structural protein 1 (NSP1), exhibits the greatest sequence variability of any of RV protein. Although non-essential for RV replication in cell culture, NSP1 has been suggested as a virulence factor modulating the host innate immunity. RV NSP1-mediated ability to modulate the IFN response is conserved between strains infecting different species, however, it has been reported that targets within the induction and signalling pathways vary between strains. NSP1 derived from viruses infecting monkeys (RRV, SA) and mice (EW) appear to preferentially target IRF-3 to induce its proteasome-mediated degradation, while NSP1 of porcine origin (OSU) targets β-TrCP, preventing NF-κB activation. In contrast, NSP1 from RV strain UKtc infecting cattle appears to target both IRF-3 and β-TrCP. In order to establish if the observed RV host-range restriction is related to the ability of NSP1 to selectively target different components of the IFN pathways, Y-2-H analysis were performed. A panel of NSP1 derived from RV infecting different mammal species were tested for their binding ability against components of the IFN induction pathway. Indeed NSP1 showed a strain-dependent ability to interact with IRF-3. A series of luciferase reporters have shown that NSP1 was able to downregulate the induction of type I and type III IFNs at their transcriptional level and how this downregulation varied between NSP1 derived from different strains. In addition, NSP1 appeared to target the IFN signalling pathway, blocking ISGs transcription. Moreover, NSP1 showed a strain-dependent expression level.
Supervisor: Iturriza-Gomara, Miren ; Blake, Neil ; Seago, Julian ; Jackson, Ben Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral