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Structural Studies of Non-Enveloped Viruses Associated with Human Diseases

Hurdiss, Daniel Luke (2018) Structural Studies of Non-Enveloped Viruses Associated with Human Diseases. PhD thesis, University of Leeds.

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Abstract

Non-enveloped viruses encompass many human pathogens which are responsible for a broad range of diseases that have very significant impacts on human health. By studying the structures of such viruses, insights can be gained into aspects of their lifecycle, including receptor attachment, genome uncoating and capsid assembly. This information can then serve as a structural platform for the design of targeted antivirals and vaccines. This thesis aimed to use cryo-electron microscopy (cryo-EM) to structurally characterise the structures, and receptor binding, of two important human pathogens, BK polyomavirus (BKV) and Coxsackievirus A24v (CV-A24v). BKV causes polyomavirus-associated nephropathy and haemorrhagic cystitis in immunosuppressed patients. These are diseases for which we currently have limited treatment options. Initially, a modest resolution structure (~7 Å) of BKV is used to investigate the organisation of the viral genome and minor capsid proteins. Subsequently, high-resolution structures of BKV alone (3.8 Å) and in complex with the receptor fragment of GT1b ganglioside (3.4 Å) and heparin (3.6 Å) were determined. Collectively, these structures provide insights into capsid assembly, rationalise how GT1b enhances infection over smaller gangliosides studied previously and provide the first structural clues for glycosaminoglycan binding to BKV. CV-A24v is responsible for large outbreaks of acute haemorrhagic conjunctivitis (AHC), a painful, contagious eye disease. Here, ICAM-1 is identified as an essential receptor for CV-A24v and the high-resolution cryo-EM structure (3.9 Å) of the virus–ICAM-1 complex is presented, which reveals the critical ICAM-1–binding residues within the capsid. These data could help identify a possible conserved mode of receptor engagement among ICAM-1–binding enteroviruses. In addition, structures of the uncoating intermediates of CV-A24v are presented which describe the molecular basis of capsid expansion. Furthermore, the molecular details of a branched pocket factor binding site in CV-A24v are described which is unique amongst currently structurally characterised human enteroviruses.

Item Type: Thesis (PhD)
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Keywords: Cryo-electron microscopy, BK polyomavirus, Human pathogens, Virology, Structural virology, Virus-host interactions, Glycobiology, Polyomavirus-associated nephropathy, Haemorrhagic cystitis, Conjunctivitis, Coxsackievirus A24v, Receptors, ICAM-1, Sialic acid, Enterovirus, Genome uncoating
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds) > Institute for Molecular and Cellular Biology (Leeds)
Depositing User: Dr Daniel L Hurdiss
Date Deposited: 19 Dec 2018 10:59
Last Modified: 19 Dec 2018 10:59
URI: http://etheses.whiterose.ac.uk/id/eprint/22406

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