Krause, Melanie Erika Susanne;
(2020)
Vaccinia Virus Modulation of Host Cell Autophagy.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
PhD_MK.pdf - Accepted Version Download (132MB) | Preview |
Abstract
Poxviruses are the most complex mammalian viruses, encoding over 200 genes and replicating exclusively in the host cytoplasm. This virus family includes variola virus, the deadliest pathogen that ever existed, and vaccinia virus (VACV), the vaccine used for its eradication. Now VACV is used to study host-pathogen interactions, as a vaccine vector against other pathogens and for oncolytic immunotherapy. Autophagy is used by cells as a defence mechanism to engulf and destroy pathogens. Being a cytosolic virus, vaccinia, must circumvent this process for successful replication. It has been demonstrated that autophagy is not needed for successful VACV replication and that VACV induces LC3 lipidation in the absence of ATG5 and ATG7. Thus, during VACV infection, autophagy is activated as a defence mechanism, while the virus encodes factors that serve to counteract its inhibitory action. During my PhD I showed that VACV modulating drugs impact VACV production and spread. An RNAi based screen was utilized to identify several VACV proteins that potentially impact LC3 lipidation. Furthermore, I show that several autophagy receptor proteins are modulated during VACV infection. p62/SQSTM1 initially targets VACV during early stages of infection before being shunted to the nucleus via direct V ACV induced phosphorylation. Overexpression of p62 reduces VACV yield and modification of the p62 nuclear localization signal abrogates the translocation process leading to p62 targeting of VACV replication sites. Interestingly, inhibition of nuclear import of p62 coincides with a drastic decrease of VACV infectivity. Additionally, I observed that the receptors NDP52 and Tax1Bp1 are degraded during VACV infection. This work suggests that VACV exhibits a unique multi-layered control of autophagy to avoid elimination.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Vaccinia Virus Modulation of Host Cell Autophagy |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10093582 |
Archive Staff Only
 |
View Item |
