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Title: The triggers and mechanism of apoptosis in mammalian cells infected with Semliki Forest virus
Author: Barry, G. M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2008
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This thesis uses the alphavirus Semliki Forest virus (SFV) to investigate mechanism(s) of virus induced apoptosis. Cell death in response to SFV infection is apoptotic, although perhaps not completely caspase dependent. During infection membranes of the mitochondria are disrupted, mitochondrial membrane potential is lost and caspases- 3, -8 and -9 are activated. Fas, RNase-L, ISG-12 and PKR are not required for cell death. PKR is however a strong inhibitor of early virus production; relative to wt mouse embryo fibroblasts (MEFs), MEFs with a disruption of the PKR gene produce SFV more rapidly and die more rapidly. Cellular detection of dsRNA can trigger signal transduction cascades resulting in activation of interferons, pro-inflammatory cytokines and pro-apoptotic pathways. Inhibition of these dsRNA induced cascades delays death of SFV infected cells demonstrating that detection of virus RNA replication is one trigger of apoptotic cell death. Synthesis of virus glycoproteins is not required for, but contributes to, cell death. SFV structural proteins build up in the endoplasmic reticulum triggering the unfolded protein response and activating the pro-apoptotic proteins caspase-12 and CHOP. In summary, SFV infection of continuously cultured mammalian cells in vitro leads to caspase activation and apoptotic cell death. The apoptosis is triggered by the detection of dsRNA as well as the virus structural proteins building up in the ER; other factors may also play a role.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available