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Title: Identification of novel accessory proteins encoded by influenza A virus segment 2 that prevent interferon induction
Author: Pinto, Rute Maria Dos Santos
ISNI:       0000 0004 8508 7693
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Influenza A viruses (IAV) are a major group of pathogens that infect a broad range of mammalian and avian species and in humans, cause of annual epidemics and occasional pandemics. IAVs are orthomyxoviruses containing an 8 segment negativesense single-stranded RNA genome encoding 10 core polypeptides essential for virus replication. Alternative translation events that produce additional viral polypeptides have been shown to be significant in IAV biology. IAV genome segment 2 is a virulence determinant known to encode PB1, PB1- F2 and PB1-N40 proteins, starting from AUG codons 1, 4 and 5 respectively. Work in this thesis investigated the expression of two additional polypeptides, arising from translation initiation at AUGs 10 and 11 of segment 2. These codons are highly conserved in IAV and direct the translation of two N-terminally truncated versions of the primary PB1 product (PB1-N92 and -N111 respectively). Mutation of AUGs 10 or 11 in the background of the A/PR/8/34 strain had minor effects on virus replication kinetics despite giving elevated levels of IRF3 phosphorylation and type I IFN secretion compared to the WT virus. However, simultaneous mutation of AUGs 10 and 11 severely decreased viral fitness. Similar patterns of defective replication and elevated innate signalling were seen when mutating AUGs 10 and/or 11 in other mammalian virus isolates. The propagation deficit of the PR8 ΔAUG10,11 mutant recovered in IFN-deficient models, including IFN α/β receptor (IFNAR) knockout bone marrow-derived macrophages and in vivo in IFNAR-/- mouse lungs. Moreover, expression of PB1-N92 or -N111 polypeptides blocked poly I:C- and TBK1-, but not IRF3-induced activation of the IFN-β promoter in transfected cells, suggesting the polypeptides blocked innate immune signalling downstream of RIG-I-like receptor signalling but upstream of IRF3 phosphorylation. Consistent with this, addition of a TBK1/IKKε inhibitor increased growth of the mutant viruses. In conclusion, IAV segment 2 expresses two previously undescribed Nterminally truncated versions of PB1 which play a role in antagonising the host IFN response, most likely at the stage of the TBK1/IKKε complex.
Supervisor: Digard, Paul ; Dutia, Bernadette Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: influenza A viruses ; avian influenza viruses ; host immune response ; host protein synthesis ; PB1-N92 ; PB1-N111 ; IAV segment 2 ; interferon response