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Defining factors that influence vaccinia virus spread and fusion

Beerli, Corina; (2018) Defining factors that influence vaccinia virus spread and fusion. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Vaccinia virus (VACV), a large double-stranded DNA virus, is a close relative of smallpox virus. Two distinct infectious forms of virions are produced by VACV: Single-membrane mature virions (MVs) and double-membrane enveloped virions (EVs). VACV is thought to exploit cell motility as a means to enhance the spread of infection. A single viral protein, F11, contributes to this by mediating the inhibition of RhoA signalling in order to facilitate cell retraction. However, F11 is not sufficient for VACV-induced cell motility, indicating that additional viral factor(s) must be involved. We showed that vaccinia virus growth factor (VGF), a homologue of EGF, promotes infected cell motility to facilitate the spread of infection. We found that VGF secreted from early infected cells is cleaved by the metalloprotease ADAM10 whereupon it acts largely in a paracrine fashion to direct cell motility. Real-time tracking of cells infected in the presence of EGFR/MEK/FAK/ADAM10 inhibitors, or with VGF and F11 deleted viruses, revealed defects in radial velocity and directional migration efficiency during plaque formation, leading to impaired cell-to-cell spread of infection. Intravital imaging showed that virus spread and lesion formation are attenuated in the absence of VGF. These results demonstrate how poxviruses hijack EGFR-induced cell motility to promote rapid and efficient spread of infection in vitro and in vivo. In addition, we developed the open-source software VirusMapper that combines super-resolution microscopy and single-particle averaging to map the localisation of proteins within viral particles. We found that the viral entry fusion complex (EFC) localises to the tips of virions. Furthermore, we found that infected cells produce VACV-triggered extracellular vesicles (VEVs) that contain EV membrane proteins but are devoid of virions. VEVs are phosphatidylserine-positive, suggesting that they may use apoptotic mimicry to dampen the immune response of neighbouring cells, thereby enhancing virus spread.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Defining factors that influence vaccinia virus spread and fusion
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/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/10063875
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