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dc.contributor.advisorVazquez-Boland, Jose
dc.contributor.advisorCavanagh, David
dc.contributor.authorMacArthur, Iain
dc.date.accessioned2018-01-11T10:28:33Z
dc.date.available2018-01-11T10:28:33Z
dc.date.issued2016-07-02
dc.identifier.urihttp://hdl.handle.net/1842/25895
dc.description.abstractThe pathogenic actinomycete Rhodococcus equi is a facultative intracellular parasite that replicates within macrophages. This ability is dependent on the pVAP virulence plasmid, and more specifically, on the laterally acquired vap pathogenicity island (vap PAI) carried by it. R. equi has two contrasting lifestyles as a soil-dwelling microbe and as an inhabitant of the intracellular macrophage compartment. In the first part of this thesis work we analysed the nature of the signals recognised by R. equi to adapt the expression of the virulence genes of the plasmid during the transition from soil saprotroph to intracellular parasite. The expression profile of virulence plasmid genes in response to temperature and pH in vitro and to the macrophage environment was investigated by microarray analysis. A shift to 37ºC was the main stimulus involved in vap PAI gene activation and macrophage-derived signals did not further modulate the expression of the PAI genes contrary to previous suggestions. In a second part of the thesis we investigated the role of a horizontally acquired island encoding exopolysaccharide biosynthesis in the R. equi saprotroph-intracellular parasite dual lifestyle. Mutational analysis of this locus showed that it is responsible for the typical mucoid colony morphology of R. equi and the ability to produce a polysaccharide capsule. Mutations in the capsule locus favoured macrophage uptake but had no effect on intracellular proliferation and in vivo survival in mice. However, the capsule mutants showed significantly increased susceptibility to desiccation, ultraviolet radiation and heat and were outcompeted by capsulated wild-type R. equi in dry soil. Thus, while having a minor role in virulence, the R. equi capsule appears to be primarily required for survival in soil and to act as a transmission factor. The third part of this work followed the identification of a horizontally acquired locus that encodes pili appendages that promote association with macrophages and colonization of the mouse lung. The ability of a component of this structure, the RplB pilin subunit, to act as a vaccine antigen was investigated in mice and horses. Vaccinated mice produced high levels of anti-RplB IgG and showed significant protection against pulmonary challenge with virulent R. equi. The experimental RplB subunit vaccine proved also to be immunogenic in horses, eliciting a strong IgG response in pregnant mares and foals. We also demonstrated passive transfer of high levels of maternal anti-RplB antibodies from the mares to the foals via colostrum. Our results indicate that the RplB pilin subunit is a promising novel candidate R. equi vaccine antigen.en
dc.contributor.sponsorotheren
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionAnastasi, E., Giguere, S., Berghaus, L. J., Hondalus, M. K., Willingham-Lane, J. M., MacArthur, I., Cohen, N. D., Roberts, M. C. & Vazquez-Boland, J. A. 2015. Novel transferable erm(46) determinant responsible for emerging macrolide resistance in Rhodococcus equi. Journal of Antimicrobial Chemotherapy, 70, 3184-90.en
dc.relation.hasversionGonzalez-Iglesias, P., Scortti, M., Macarthur, I., Hapeshi, A., Rodriguez, H., Prescott, J. F. & Vazquez-Boland, J. A. 2014. Mouse lung infection model to assess Rhodococcus equi virulence and vaccine protection. Veterinary microbiology, 172, 256-64.en
dc.relation.hasversionLetek, M., Gonzalez, P., Macarthur, I., Rodriguez, H., Freeman, T. C., Valero-Rello, A., Blanco, M., Buckley, T., Cherevach, I., Fahey, R., Hapeshi, A., Holdstock, J., Leadon, D., Navas, J., Ocampo, A., Quail, M. A., Sanders, M., Scortti, M. M., Prescott, J. F., Fogarty, U., Meijer, W. G., Parkhill, J., Bentley, S. D. & Vazquez-Boland, J. A. 2010. The genome of a pathogenic rhodococcus: cooptive virulence underpinned by key gene acquisitions. PLoS genetics, 6.en
dc.relation.hasversionMacArthur, I., Parreira, V. R., Lepp, D., Mutharia, L. M., Vazquez-Boland, J. A. & Prescott, J. F. 2011. The sensor kinase MprB is required for Rhodococcus equi virulence. Veterinary microbiology, 147, 133-41.en
dc.relation.hasversionValero-Rello, A., Hapeshi, A., Anastasi, E., Alvarez, S., Scortti, M., Meijer, W. G., Macarthur, I. & Vazquez-Boland, J. A. 2015. An invertron-like linear plasmid mediates intracellular survival and virulence in bovine isolates of Rhodococcus equi. Infection and immunity.en
dc.relation.hasversionVazquez-Boland, J. A., Giguere, S., Hapeshi, A., Macarthur, I., Anastasi, E. & Valero-Rello, A. 2013. Rhodococcus equi: the many facets of a pathogenic actinomycete. Veterinary microbiology, 167, 9-33.en
dc.subjectvirulenceen
dc.subjectcapsuleen
dc.subjectvaccineen
dc.subjectRhodococcus equien
dc.titleAnalysis of Rhodococcus equi surface-associated survival determinants identified in the genome and their exploitation as vaccine targetsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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