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Title: Analysis of human respiratory syncytial virus-host cell interactions
Author: Munday, Diane Carolyn
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Human respiratory syncytial virus (HRSV) is the leading cause of serious lower respiratory tract disease in infants worldwide. Other high risk groups include the elderly and immunocompromised but HRSV can cause disease in all ages and infections recur throughout life. There is no approved vaccine available and costly antiviral therapies are inefficient for general use. HRSV infection therefore presents a significant healthcare and economic burden. The aims of this study were to investigate the HRSV-host cell interactions and examine the host response to infection via alterations to .the cellular proteome with a view to identifying the pathways, processes and organelles which play a key role in virus infection. Viral RNA synthesis and virion assembly occur in the cytoplasm inducing a stress response as replication alters host cell gene expression. To study this, large scale quantitative proteomics was used to analyse HRSV interactions with cytoplasmic, nuclear and mitochondrial proteomes. Underpinning this was stable isotope labelling with amino acids in cell culture (SILAC) coupled to LC-MS/MS, allowing the simultaneous identification and quantification of cellular and viral proteins. Canonical pathways and specific protein abundance and/or re-localisation changes highlighted by the data sets were validated and characterised using immunoblot analysis, confocal microscopy and functional assays. This allowed a complex picture of virus-host cell interactions to be assembled: novel changes in cell cycle proteins, sub-nuclear structures and mitochondrial function were observed. Proteins involved in the immune proteins converged on mitochondria in HRSV-infected cells and mitochondrial proteome alterations led to the functional analysis of the mitochondrial receptor, Tom70 and its chaperone Hsp90 which were found to play antiviral and pro-viral roles in HRSV biology, respectively. The findings of this study have increased our understanding of the cellular the pathways, processes and organelles which play key roles in RNA-virus infection and highlighted potential targets for therapeutic intervention.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available