Picornaviruses are non-enveloped, positive sense single-stranded RNA viruses which cause many diseases ranging from slight illness to fatal meningitis and encephalitis. There are no vaccines against most picornaviruses so drugs need to be developed. Human parechoviruses (HPeVs) are being increasingly recognised as important human pathogens, but are genetically diverse from other picornaviruses. We therefore need to understand the details of virus replication to improve the opportunities to develop antiviral drugs. Viruses often rearrange the ER, ERGIC and Golgi to give a new membrane structures involved in viral replication and/or assembly. To improve our understanding of HPeV replication, we first studied the secretory pathway compartments and we found in HPeV-infected cells that the Golgi was rearranged and became more concentrated near to the replication complex. ER seemed to disappear almost completely. In terms of HPeV non-structural proteins, 2C had a major effect on the compartments and also co-localised and aggregated lipid droplets. Many viruses such as hepatitis C virus (HCV) and Dengue virus recruit lipid droplets to replication complexes. We found that lipid droplets became larger in HPeV-infected cells, but do not co-localise with replication complexes. To investigate the interaction between 2C and lipid droplets we made several 2C mutants. Mutation of NTPase domain of 2C did not change the interaction with lipid droplets. Instead we found that other domains, including a novel amphipathic helix are important. The results suggest that lipid droplets play a role in HPeV replication and so we investigated the effect of drugs which target lipid droplet formation and lipid homeostasis on HPeV replication. We demonstrated that drugs which target the enzyme DGAT1, which is involved in lipid droplet formation, have a potent effect on HPeV replication. Our results suggest that blocking lipid droplet formation is could be an important strategy for the treatment of HPeV infection.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:712541 |
| Date | January 2016 |
| Creators | Khrid, Ali A. S. |
| Publisher | University of Essex |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://repository.essex.ac.uk/19643/ |
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