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Title: Nramp1 genotype, stress and the immunopathogenesis of intracellular parasitism
Author: Evans, C. A. W.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2000
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The natural resistance associated macrophage protein gene (Nramp1) influences susceptibility to several intracellular infections. To investigate the mechanism of this effect, congenic Nramp1 wild type (infection resistant) and mutant (infection susceptible) mice were infected with Leishmania donovani. The Nramp1 mutant mice developed more severe infection. Quantitative RT-PCR and fluorescence microscopy demonstrated that the mutant mice had attenuated hepatic chemokine and pro-inflammatory cytokine innate immune responses, reduced hepatic cellular infiltrate, reduced hepatic apoptosis and abnormal accumulation of cellular iron. This validated methodology was used to investigate the function of Nramp1 in cerebral infection. Following Toxoplasma gondii infection, mutant mice had significantly greater mortality. Laboratory analysis demonstrated for the first time that the naturally occurring infection-susceptible mutation in Nramp1 attenuates brain expression of chemokines, pro-inflammatory and immuno-regulatory cytokines in response to infection. During this research, it was noted that Nramp1 genotype also affected the behavioural stress response and this was investigated using restraint stress and quantitative in situ hybridisation. Compared with wild type mice, Nramp1 mutant mice had larger adrenal glands and higher circulating corticosterone concentrations but their hypothalamic, adrenal and behavioural stress responses following restraint stress were reduced. This abnormal stress response in Nramp1 mutant mice was associated with restraint stress increasing susceptibility to T. gondii infection in aged but not young mice. Immunochemical studies suggested that the Nramp1 protein was expressed on cerebral neurones as well as cells of the monocyte/macrophage lineage.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available