Prevalent worldwide, the protozoan parasite, Toxoplasma gondii, is an important cause of spontaneous abortion, ocular disease, mental retardation and encephalitis. Currently there are no human vaccines available. The first major aim of this study was to test potential HLA restricted peptide vaccines, previously shown to be protective in HLA-transgenic mice, against oocyst infection. The ability of entrapment within non-ionic surfactant vesicles to improve the efficacy of the HLA-B*0702 restricted vaccine was also studied. In parallel we tested the novel T. gondii ΔRPS13 live-attenuated vaccine against oocyst challenge. As determined by survival, only ΔRPS13 provided a measure of protection against oocyst challenge. We also demonstrated that the live vaccine induced a greater CD8+ T cell effector response than the adjuvanted peptide vaccine. Successful vaccination is in large part dependent on inducing an appropriate response in the primary host cell populations that consequently influences the development of adaptive immunity. Parasite induced macrophage arginase-1 expression, for example, has been shown to be influential during T. gondii infection. Arginase-1 expression is negatively regulated by Map Kinase Phosphatase-2 (MKP-2), the second major aim of the project was to study the effect of MKP-2 deficiency on T. gondii infection. MKP-2-/- mice were found to be more susceptible to infection with increased parasite growth and increased mortality compared with wild type mice. Increased susceptibility was associated with reduced serum nitrite levels and enhanced tissue arginase-1 expression although the Th1 response was unaltered. In vivo inhibition of iNOS and arginase-1 revealed that while NO production is of paramount importance in controlling parasite growth arginase-1 could also limit parasite growth independently. In vitro studies utilising macrophages confirmed a role for arginase-1 in parasite control. Results highlight a complex interaction between iNOS and arginase-1 and T. gondii in L-arginine metabolism but indicate that manipulation of early infection events influence disease outcome.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:576375 |
| Date | January 2012 |
| Creators | Woods, Stuart |
| Publisher | University of Strathclyde |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=19276 |
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