Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.724919
Title: Structural characterisation of the foot-and-mouth disease virus uncoating pathway
Author: Malik, Nayab
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Abstract:
Foot-and-mouth disease virus is a single-stranded RNA virus that belongs to the genus aphthoviruses, in the family Picornaviridae, and causes disease in cloven-hoofed animals. It is one of the biggest hindrances to the international trade of animals and animal products in the world. The virus capsids readily dissociate into pentamers at acidic pH. While there have been several studies on enterovirus uncoating, this process is poorly-understood for aphthoviruses, and there are no published structures elucidating how FMDV undergoes this transformation to infect cells. Furthermore, there are no structures available for a dissociated FMDV pentamer. Thus far, there has been only one paper claiming to show, at low resolution, a disassembly intermediate for another aphthovirus, Equine Rhinitis A Virus (ERAV). Here, a 5.2Å-structure of an FMDV assembly formed from acid dissociated pentamers, visualised using cryo-electron microscopy (cryo-EM), is presented. This inside-out assembly of the pentamers highlights the extensive conformational changes in the pentamers that may have lead to the disassembly of the native capsid. Also presented here is a lower-resolution structure of the isolated dissociated pentamer (8.2 Å), enabling a comparison of the differences between native FMDV particles, the dissociated- and the re-assembled pentamers. These analyses elucidate why the pentamers may have been unable to re-assemble properly. Together, these data suggest that the ERAV structure mooted to be a disassembly intermediate may have formed from re-assembled dissociated pentamers. Furthermore, it is concluded that there is still no hard structural evidence that aphthoviruses form an intermediate particle during disassembly. The thesis also includes high-resolution cryo-EM structures of the FMDV serotypes SAT1 and SAT3 (3.8 Å and 3.1 Å respectively), derived from inactivated virus-pellets, thus completing the repository of high-resolution structures for all SAT serotypes. The results provide an insight into the reasons for SAT3 being the most thermally-unstable picornaviruses, and also include predictions and comparative analyses with known antigenic sites of other FMDV serotypes.
Supervisor: Stuart, David I. ; Huiskonen, Juha Sponsor: Nuffield Department of Medicine
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.724919  DOI: Not available
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