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Enteroviral modulation of host cell and drug-induced apoptosis.

Salako, Michael Albert. (2005) Enteroviral modulation of host cell and drug-induced apoptosis. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

Coxsackievirus B4 (CVB4) is a common infection. Most cases are symptom-free but occasionally chronic sequelae emerge such as insulin-dependent diabetes mellitus, and dilated myocardiopathy and virus persistence is thought to contribute to these conditions. Persistent viruses frequently possess mechanisms that promote survival of the infected cell and inhibit apoptosis. Mitochondria play a central role in mediating apoptotic effects and may thus be targeted by viruses. Recently, poliovirus was shown both to inhibit apoptosis and to disrupt mitochondrial function and thus we have sought similar effects in the related virus CVB4. CVB4 infection of HeLa cells did not disrupt mitochondrial function and energy levels were maintained. In contrast to cells entering apoptosis, mitochondrial membrane potential increased after infection; at the same time infected cells developed resistance to drug-induced apoptosis via both death receptor and mitochondrial pathways. Despite this resistance, the apoptotic machinery was fully activated by drug treatment of infected cells and the processing of procaspase-3 to its cleaved form (caspase-3) was normal. However, DEVDase activity was inhibited in drug-treated CVB4 infected cells and extracts from infected cells suppressed the activity of recombinant caspase-3 in vitro. We conclude that this effect was mediated at least in part by virus protein 2BC since immunoprecipitation of caspase-3 from infected cells co-precipitated a 2BC-sized (48kDa protein). Further, protein 2BC expressed in vitro was shown to bind to caspase-3, and expression of 2BC alone in HeLa cells led to the inhibition of caspase-3 activity. Taken together these data imply that CVB4 protein 2BC acts to mitigate the consequences of apoptosis induction by associating with caspase-3 and inhibiting its function. These results suggest that 2BC is acting as a viral IAP and this is the first report of such an ability for an RNA virus.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors :
NameEmailORCID
Salako, Michael Albert.UNSPECIFIEDUNSPECIFIED
Date : 2005
Contributors :
ContributionNameEmailORCID
http://www.loc.gov/loc.terms/relators/THSUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Depositing User : EPrints Services
Date Deposited : 09 Nov 2017 12:14
Last Modified : 09 Nov 2017 14:41
URI: http://epubs.surrey.ac.uk/id/eprint/843342

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