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Investigating the role of vaccinia virus binding proteins in host cell entry

Pokorny, Laura; (2021) Investigating the role of vaccinia virus binding proteins in host cell entry. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Poxviruses enter cells using the most complex binding and fusion machinery identified to date. Studies indicate that vaccinia virus fusion relies on eleven, and binding on at least four, distinct proteins. Understanding, and subsequently blocking, viral entry is the first and most effective line of defence we have against infection. Therefore, in-depth knowledge of this complex process is paramount. The development of new and effective tools to aid the study of virus entry is important. To this end, I developed a minimal model system based on cell-derived membrane blebs. Blebs are advantageous due to their smooth surface, small size and the fact that they retain the original cell surface composition. Using this system, I found that VACV virions bind in a side-on orientation, and that this can be altered to become more tip bound by removing a subset of the binding proteins. Blebs also enabled the identification of a novel VACV, cellular membrane remodelling mechanism. Under low-pH conditions the binding protein D8 induces cellular membrane invagination. During virus entry via low-pH dependent macropinocytosis this membrane remodelling promotes productive infection by increasing the contact between the limiting membrane of the macropinosome and the viral fusion machinery which is found exclusively at the tips of the virion. From these findings, I conclude that VACV binding and fusion are more intimately linked than first thought. Furthermore, I characterised VACV binding to an unprecedented degree revealing hierarchies and redundancies between the four binding proteins. The high level of redundancy and the ability of the virus to adapt to the binding environment presented on target cells is likely to account for the cell-type and host promiscuity displayed by VACV.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating the role of vaccinia virus binding proteins in host cell entry
Event: UCL
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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/10119925
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