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Title: Dysregulation of parainfluenza virus 5 RNA synthesis and consequences for interferon induction
Author: Pickin, Matthew John
ISNI:       0000 0004 7962 5248
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2019
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The front-line defence against viral infection is the innate immune response. A crucial component of the innate immune system is type I interferon (IFN) which is induced when pathogen recognition receptors (PRRs) activate signalling cascades, following recognition of pathogen-associated molecular pattern (PAMP)s. The crucial PRRs for the IFN response to RNA viruses are RIG-I (retinoic acid inducible gene I) and MDA5 (melanoma differentiation-associated gene 5). Parainfluenza virus 5 (PIV5) is a negative-sense single-strand RNA virus of the Paramyxoviridae family. Previous work from our group has demonstrated that “copy- back” defective interfering (DI) genomes constitute a major PAMPs produced by PIV5. The aim of this study was to examine whether PIV5 can also generate PAMPs distinct from DI genomes. To do this we have generated viruses that have been engineered to increase PAMP production and have compared IFN induction between these viruses and equivalent viruses unable to express a full-length V protein, the IFN antagonist. To examine which PRRs are important for IFN induction by PIV5 and the engineered viruses, an A549 reporter cell line, incorporating GFP under the control of the IFN-beta promoter, was used as the parental line to knock-out RIG-I and MDA5 using CRISPR/Cas-9 nucleases. A virus with two nucleotide changes in the Leader region caused an altered RNA production profile which was accompanied by a RIG-I-dependent increase in IFN induction, despite the virus expressing full-length V protein. The PAMP responsible appeared to be distinct from DI genomes. A virus with an amino acid change within the P protein, a subunit of the viral polymerase, augmented the viral RNA profile, leading to increased levels of IFN induction, and again RIG-I was responsible for the elevated IFN response, although the nature of the PAMP remains to be determined.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available