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Foot-and-mouth disease viruses (FMDVs) constitute the aphthovirus genus of the Picornaviridae. The structures of Oi subtype viruses OiK and G67 have been solved and comparisons reveal the structural basis of monoclonal antibody escape mutations in G67. Escape mutations are seen to occur at surface-exposed residues and to provoke structural changes limited to the altered side chains. Comparisons of the structures of O₁ and O₁BFS (Acharya et al., Nature 337, 709-716 (1989)) suggest that changes occurring 'in-the-field' in response to polyclonal antibody pressure may be subtly different from mutations produced by monoclonal antibody pressure in vitro. Field mutations are seen to alter less exposed residues and to have more far-reaching structural effects than the in vitro, monoclonal provoked mutations. Crystals of G67 are seen to be 'intimately twinned', the data possessing extra symmetry due to a mis-packing of the crystals. A protocol, based on current real-space averaging procedures with a novel constraint imposed, has been used successfully to deconvolute these data. This method might be more generally applied to deconvolute the wavelength overlaps that occur when using the Laue method. The structures of C-S8cl and mutant SD6-6 have been solved at a resolution of 3.5Å. These structures enable comparisons between members of different FMDV serotypes to be made for the first time, namely: serotype 0 (O₁BFS) and serotype C (C-S8cl). Flexibility of the Arg-Gly-Asp containing G-H loop of VP1 is seen to be amongst the most conserved structural features. This loop is implicated in receptor binding and possible roles for the observed flexibility are discussed. The CS8cl structure also reveals more detail in previously disordered regions of the capsid, namely: the N-terminal residues of VP2 and potential myristate density under the 5-fold axis of the virion. Analysis of structures from the Protein Data Bank reveals different patterns of amino acid use in proteins involved in the two halves of the immune recognition event i.e. immunoglobulins and viruses. These patterns seem to be based not only on the characteristics of the most used amino acids but also on characteristics of the nucleotide codons used to code for them.

Foot-and-Mouth Disease Virus (FMDV) is a globally important pathogen responsible for causing Foot-and-Mouth Disease (FMD) in wildlife and domestic livestock species and has significant economic impacts. FMD is difficult to control due to its highly infectious nature, wide diversity of host species and the existence of multiple serotypes; therefore, understanding the processes of FMDV infection and viral RNA replication are key to the development of improved diagnostics and vaccines. This thesis investigates the potential roles of the FMDV 3A non-structural protein using a combination of sub-genomic replicons, recombinant viruses and proteomics techniques. The picornavirus 3A protein has previously been linked with roles in replication complex formation, virulence and determining viral host range. This thesis presents findings showing that a naturally occurring deletion in 3A had differing effects on replication in cells lines derived from different natural hosts thereby supporting the conclusion that 3A has an important role in viral host range. Proteomic (immunoprecipitation and mass spectroscopy) investigations were carried out to identify potential cellular interaction partners of FMDV 3A, and the impact on infection and replication of reducing expression of two selected cellular proteins Rab7L1 and TBC1D20 was investigated. The 3A protein of FMDV was shown to include a conserved FFAT motif (which bind the ER resident protein VAP) in its N terminal domain. A role for this motif was also investigated with the results suggesting that the 3A FFAT motif is important for efficient viral replication. Finally, the potential role of 3A to act as the donor of 3B during replication was investigated. Key findings from experiments using FMDV replicons and recombinant viruses showed that full-length P3 and the processing intermediate 3ABBB are not required for viral RNA replication suggesting that the preferred donor of 3B for uridylation is likely a 3BC containing precursor protein.

Please read the abstract in the section 00front of this document / Thesis (PhD (Microbiology))--University of Pretoria, 2007. / Microbiology and Plant Pathology / unrestricted

No description available.

Thesis (Ph.D.)(Bioinformatics))--University of Pretoria, 2008. / Includes summary.

Thesis (Ph. D.)--Washington State University, August 2008. / Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 134-158).

Thesis (M.Sc.)(Microbiology)--University of Pretoria, 2006. / Includes summary. Includes bibliographical references. Available in print and online.

Thesis (Ph.D.) - University of St Andrews, August 2008.