School of Biomedical Sciences - Theses
Permanent URI for this collection
Search Results
1 - 1 of 1
-
ItemImpact of respiratory syncytial virus infection on host mitochondrial organisation and function( 2018)Respiratory syncytial virus (RSV), a leading cause of acute lower respiratory illness in infants, immunosuppressed adults and the elderly, is responsible for more deaths each year than influenza. Despite this, there are no freely available treatment options, making the development of safe and efficacious anti-RSV therapeutics a high priority. However, in order to achieve this, a deeper understanding of the RSV-host cell interaction is required. RSV infection has previously been found to induce global changes in the mitochondrial proteome and interfere with mitochondria-mediated antiviral signalling, but details of the RSV-host cell mitochondrial interaction are poorly understood. Therefore, the aim of this thesis is to explore the impact of RSV infection on host mitochondria and its role in viral pathogenesis in order to identify novel anti-RSV strategies. The results presented in this thesis reveal for the first time that RSV induces a staged, microtubule/dynein-dependent redistribution of mitochondria, concomitant with reduced mRNA levels of genes encoding mitochondrial proteins, compromised mitochondrial respiration, dissipated mitochondrial membrane potential (Δѱm), and increased generation of mitochondrial reactive oxygen species (ROS). It was also found that inhibiting mitochondrial redistribution or mitochondrial ROS production strongly suppressed RSV virus production, highlighting the RSV-mitochondrial interface as a potential antiviral target. Analysis of RSV proteins identified the matrix protein (M) is sufficient and necessary to induce mitochondrial perinuclear clustering, downregulation of mitochondrial genes, inhibition of mitochondrial respiration, loss of Δѱm, and accumulation of mitochondrial ROS in infection, while deletion and mutation studies identified its central nucleic acid-binding domain, and arginine/lysine residues 170/172 in particular, as essential for its remodelling ability in host cell mitochondria. Recombinant RSV carrying the arginine/lysine mutations in M was unable to elicit these effects on host mitochondria, and its replication in infected cells was severely impaired, underlining the importance of M-dependent effects on mitochondria to RSV infection. Importantly, clinically relevant human cell models of RSV infection were examined, highlighting the importance of RSV’s impact on host mitochondria to its infectious cycle, and its relevance to human disease. Further, inhibiting the accumulation of mitochondrial ROS in infected cells was confirmed as a viable anti-RSV approach in these systems, and work was extended to include a mouse model that showed significantly reduced RSV-related pathology as a result of treatment with a mitochondrial ROS scavenger. In summary, the studies presented in this thesis shed new light on the impact of RSV infection on host cell mitochondria by establishing the unique ability of RSV, facilitated by the M protein, to co-opt the host cell mitochondria to enhance virus production. In addition, the importance of RSV’s impact on host mitochondria for pathogenesis is explored in multiple disease models, highlighting it as a potential target for the development of anti-RSV treatments. Significantly, the studies reveal the inhibition of mitochondrial ROS levels for the first time as a viable approach to counteract RSV infection.