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Title: Studies on the contribution of the left unique region of the genome to murine Gammaherpesvirus-68 pathogenesis
Author: Macrae, Alastair Ian
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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Due to the severe limitations on the study of gammaherpesviruses presented by their species specificity and restricted growth in vitro, infection of laboratory mice with the naturally occurring virus murine gammaherpesvirus 68 (MHV-68) has become an excellent model system for the study of gammaherpesvirus pathogenesis. This project involved the characterisation of murine herpesvirus 76 (MHV-76), another of the murine herpesviruses isolated at the same time as MHV-68. Molecular analysis revealed that MHV-76 is a deletion mutant of MHV-68, that lacks four genes unique to MHV-68 (M1, M2, M3 and M4) and eight viral tRNA-like genes that are all present at the left end of the MHV-68 genome. Biological characterisation of MHV-76, including the generation and study of rescue viruses which restored the deleted sequence into MHV-76, showed that loss of these genes leads to enhanced clearance of virus from the lungs due to a vigorous inflammatory response. There was also a significant reduction in splenomegaly and the amount of latent virus detectable in the spleen. These results show that these genes at the left end of the genome play a critical role in the viral immune evasion strategy. Detailed studies on one of these unique MHV-68 genes, M2, show that it is a 30kDa protein that has localised homology with the Gab2 and semaphorin protein families. Expression of M2 in mammalian cells reveals that it co-localises to the plasma membrane, as well as being present in diffuse areas of the nucleus and cytoplasm. Generation of a recombinant virus with a disruption in the M2 ORF showed that the M2 gene plays a critical role in the establishment of latency and the regulation of the numbers of latently infected cells in the spleen. The M2 gene is not involved in the genesis of splenomegaly. These studies uncover some of the genetic elements involved in gammaherpesvirus pathogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available