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Title: Is PB1-F2 a virulence factor for avian influenza virus in poultry?
Author: James, Joe
ISNI:       0000 0004 7657 5935
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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PB1-F2 is a small accessory protein encoded by influenza A viruses. In mammals it has been implicated in a wide range of functions which contribute to increased pathogenesis. In the avian host, PB1-F2 is understudied despite increased conservation of functional-length PB1-F2 in viruses isolated from avian compared to mammalian hosts. Therefore the aim of this thesis is to understand the contribution of the avian influenza virus PB1-F2 protein to virulence and pathogenesis in poultry. Isogenic viruses were generated that encoded a full-length or knock-out PB1-F2 protein in both H9N2 and H5N1 virus backgrounds. During experimental infection of chickens and chicken embryos, the presence of PB1-F2 correlated with reduced pathogenicity, the opposite observation published for mammalian hosts, yet prolonged infectious virus shedding, enhancing virus transmission to contact chickens. In vivo PB1-F2 coincided with a reduction in the transcript abundance of interferon stimulated genes and pro-inflammatory associated cytokines. Further in vitro characterisation identified that PB1-F2 from these avian viruses antagonises chicken type I interferon signalling and NF-κB responses through interactions with chicken variants of the signalling components MAVS and IKKβ in a similar fashion to PB1-F2 from human viruses in human cells. The potency with which each pathway was antagonised by PB1-F2 appeared to be in-part determined by the mitochondrial localisation and was strain dependent, determined by multiple residues in the C-terminal region of PB1-F2. The degree of mitochondria localisation exhibited by PB1-F2 also correlated with the ability to induce apoptosis, which in the H5N1 virus background impaired infectious virus titres. The work in this thesis leads to the hypothesis that in the avian host PB1-F2 is positively maintained due to the interaction with key innate immune proteins leading to innate immune antagonism, suppressing viral clearance and disease severity thus prolonging viral shedding and enhancing the transmission window in the field.
Supervisor: Shelton, Holly ; Barclay, Wendy ; Nair, Venugopal Sponsor: Pirbright Institute
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral