Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.772250
Title: The role of the innate immune system in a murine Gammaherpesvirus infection
Author: Thomson, Rona C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Abstract:
Members of the Gammaherpesvirinae are characterised by their ability to establish latency within lymphoid cells. Gammaherpesviruses include the human pathogens Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. Symptomatic disease and long-term persistence has been widely studied both in vivo and in vitro. However, as primary infection is largely asymptomatic, it has not been possible to determine virus-host interactions prior to the onset of symptoms. This has been further complicated by the narrow host range of the gammaherpesvirinae. Murine gammaherpesvirus-68 (MHV-68) is able to replicate in a number of cell lines in vitro and readily infects laboratory mice. It is therefore an important and flexible small animal model which provides a unique system for studying host-virus interactions at early time points post-infection. The aim of this project was to determine the role of the innate immune system in the control of gammaherpesvirus infections. It has previously been shown that type 1 interferons (IFN) are critical for host survival. RT-PCR analysis confirmed that MHV-68 infection leads to induction of type I IFN at early time points post-infection. In addition, in vitro studies indicated that type 1 IFNs play a role in the inhibition of the exit of viral particles from the cell. A strong trend towards higher titres of cell-free virus from cells lacking type I IFN receptor compared to titres of cell-free virus from wt cells was observed. IFNp knockout mice were utilised to show that IFNP is important at early time points but does not play a role in long term control of infection. MHV-76 is a deletion mutant of MHV-68, lacking four genes (M1-M4) and eight vtRNAs unique to MHV-68 and present at the left hand end of the genome. This study found no difference in the type I IFN response following infection with either MHV-68 or MHV-76. These results suggest that M1-M4 and the 8 vtRNAs do not play an extensive role in the regulation of the type 1 IFN response. IFN stimulated genes (ISGs) are important for establishing an anti-viral response. Mice lacking ISG12a were utilised to show that ISG12a plays a role in the early stages of the establishment of latency following MHV-68 infection. In vivo studies showed that virus titres and the degree of splenomegaly were increased in the spleens of lSG12a knockout mice resulting in an elevated latent infection compared to wt spleens. However, the mechanism by which ISG12a affects latency is not clear. No difference in viral titres was observed in the lungs or mediastinal lymph nodes between ISG12a knockout and wt mice. The role of NK cells was investigated by in vivo depletion ofNK cells and by monitoring NK activation following infection. The NK cell population is expanded and activated at day 2 compared to day 4 post-infection and is capable of cytotoxic killing following infection with MHV-68. However, a lack of NK cells in vivo did not result in significantly elevated virus titres suggesting that NK cells are not essential for the control of MHV-68 infection. No difference was observed between MHV-68 or MHV-76 infection in the presence or absence of NK cells, nor in the expansion or activation of NK cells post-infection. It was therefore concluded that the genes M1-M4 and the 8 vtRNAs do not play a role in the regulation of NK cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.772250  DOI: Not available
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