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dc.contributor.authorSwa, Sandien
dc.date.accessioned2018-05-14T10:16:38Z
dc.date.available2018-05-14T10:16:38Z
dc.date.issued2001en
dc.identifier.urihttp://hdl.handle.net/1842/30020
dc.description.abstracten
dc.description.abstractMalignant catarrhal fever (MCF) is a fatal, incurable disease of large ruminants. This disease is caused by two related gammaherpesviruses, Alcelaphine herpesvirus 1 (A1HV-1) and Ovine herpesvirus 2 (OvHV-2). Lymphoproliferation and infiltration by large granular lymphocytes (LGL) into lymphoid and nonlymphoid organs are characteristic of MCF. LGL cell lines have been established from animals with naturally or experimentally induced MCF. Previous studies have shown these cell lines to be highly proliferative and cytotoxic with the ability to cause disease when inoculated into rabbits. Some cell lines have demonstrated the ability to grow and survive without the need for exogenous IL-2. However, IL-2 mRNA was not detected. The proliferative and cytotoxic LGL phenotype observed in the absence of exogenous IL-2 is associated with virus infection of LGL cells. The characteristics of MCF LGL cell lines are similar to other herpesvirus-infected cell lines, in particular Herpesvirus saimiri (HVS).en
dc.description.abstractThe role of virus-infected large granular lymphocytes in pathogenesis of MCF is not clear. In the absence of defined viral antigens the main objective of this study was to investigate how MCF viruses interfere with LGL proliferation and cytotoxicity.en
dc.description.abstractIn this study, IL-2 independence and a cell surface phenotype of T/ NK cells was demonstrated in most cell lines analysed. The period of survival and growth without exogenous IL-2 was variable but always exceeded that of uninfected control cells. The possible role of IL-15 (a pro-inflammatory cytokine with actions similar to IL-2) in LGL function was investigated. Results showed that IL-15 could generate and maintain the proliferative and cytotoxic phenotype of these cell lines and may be involved in the pathogenesis of MCF.en
dc.description.abstractVirus interference with signal transduction pathways has been demonstrated in other gammaherpesviruses. The hypothesis that the phenotype and function of the LGL cell lines is generated through a similar mechanism was tested. The study showed that the src kinases, Ick and Jyn, are constitutively activated in LGL cell lines.en
dc.description.abstractThe identity of specific virus proteins involved in generating the observed phenotype of the LGL cell lines had not been determined. During the course of this x study, the complete genomic sequence of the A1HV-1 genome was published. Prior to this several open reading frames were detected in A1HV-1 that underwent genomic rearrangement on transition from virulence to attenuation in vitro. Thus, a final objective of this study was to determine whether these potential virulence genes are associated with the ability of LGL cell lines to transmit disease. The proteins encoded by these genes (ORF50, A6 and A7) were expressed in E. coli as recombinant proteins and used to immunise rabbits. Recombinant virus proteinspecific rabbit polyclonal antibodies were generated. Using these reagents, the expression of these proteins in LGL cell lines and A1HV-1-infected monolayer cultures was investigated. The polymerase chain reaction (PCR) was used in parallel experiments to determine the presence of DNA and mRNA encoding these proteins. The results indicated that more complicated rearrangements of the A1HV-1 genome may occur on attenuation of A1HV-1 after extensive passage than has been revealed at present. However, the expression in LGL cells of mRNA encoded by ORF50 and A6, that share sequence homology with the EBV R and Z transactivators, suggests that virus replication occurs in LGL cells.en
dc.description.abstractThese results improve the understanding of the MCF viruses and their role in generation of the LGL phenotype.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2018 Block 18en
dc.relation.isreferencedbyAlready catalogueden
dc.titleLarge granular lymphocyte dysregulation in Malignant Catarrhal Feveren
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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