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dc.contributor.authorMcNeilly, Tom Nathanen
dc.date.accessioned2018-05-22T12:45:21Z
dc.date.available2018-05-22T12:45:21Z
dc.date.issued2005
dc.identifier.urihttp://hdl.handle.net/1842/30497
dc.description.abstracten
dc.description.abstractThe main routes of transmission of Maedi-visna virus (MVV), an ovine lentivirus, are thought to be through ingestion of infected colostrum and/or milk, or inhalation of respiratory secretions. Whereas oral transmission appears to be mediated via uptake ofvirus by small intestinal epithelial cells, the mechanism of virus uptake in the respiratory tract is as yet unknown. Recent studies have identified intra-tracheal inoculation as a highly efficient route of experimental MVV infection compared to upper respiratory tract exposure. However it is unclear which parts of the respiratory tract are responsible for this highly efficient uptake of virus. Using an ovine tracheal organ culture model it was found that tracheal mucosa was infectable with MVV, but this infection was inefficient and non-productive, with doses of>lx 105 TCID5() required for detectable infection. Virus containing cells were located in a sub epithelial location within 12 hours post-infection, but never in the tracheal epithelium. In addition, mechanical disruption of the epithelium resulted in a significant increase in virus uptake. These results suggest that tracheal epithelium acts as a barrier to MVV uptake, and is not a primaty targetfor MVV. Immunohistochemical (II1C) analysis of tracheal mucosa identified an extensive network of sub-epithelial dendritic cells in the same location as provirus positive cells, suggesting uptake of MVV by the trachea is mediated by dendritic cells. In vivo tracking of intra-tracheal inocula using patent blue dye demonstrated exposure of both trachea and lower lung. Differential exposure of trachea and lower lung to MVV demonstrated lower lung to be significantly more efficient at MVV uptake. It was shown that virus instilled into the lower lung is taken up by alveolar macrophages (AMs), and that MVV-infected AMs are capable of transferring virus into the body. In vivo tracking of MVV infected AMs with PKII 26 dye failed to demonstrate migration of AMs from the lung airspace, suggesting that during infection, virus is transferred from AMs into the body via an indirect route. It was hypothesised that lower lung inflammation may play a key role in initial MVV entry into the body via recruitment ofviral target cells, namely macrophages and dendritic cells, and that infected AMs may play a central role in this inflammation. Real-time PCR analysis ofin vivo infected AMs demonstrated a significant up-regulation of granulocyte macrophage colony stimulating factor (GM-CSF) 7 days post-infection, but failed to demonstrate an increase in the expression of other pro-inflammatory cytokines. Histopathological, IHC and real-time PCR analysis of virus treated lung tissue failed to detect an early inflammatory response. This suggests that inflammation is not a key feature of initial virus entry, and that up-regulation of GM-CSF in AMs, which may play a role in virus entry, is a specific event and not part of a generalised inflammatory response. These results suggest that respiratory transmission of MVV may be mediated by lower lung exposure to virus, that virus is take up either by dendritic cells or AMs prior to dissemination throughout the body, and that a general inflammatory response is not required for infection via the respiratory tract.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2018 Block 19en
dc.relation.isreferencedbyAlready catalogueden
dc.titleRespiratory transmission of maedi-visna virusen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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