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Title: Defining biomarkers of protective immunity and disease for tuberculosis
Author: Hicks , Alice Sophie
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2012
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Tuberculosis (TB) is still a significant global public health problem. The only current vaccine, BCG, gives variable protection, especially in adults. Several new vaccines are currently in clinical trials but no correlates of protective immunity to TB have been defined. Therefore, vaccines have to go through extensive pre-clinical assessments and clinical trials. Once identified, correlates of protection could be used as early end-points during clinical trials, reducing costs and easing the assessment of a greater number of vaccine candidates. In addition, more reliable biomarkers of TB disease are required so that measuring the effects of therapeutic interventions during drug and vaccine trials is more accurate. A genome-wide microarray was utilised to identify potential correlates of protection induced post-BCG vaccination and post-M. tuberculosis challenge, and to identify biomarkers of disease in the non-human primate model of tuberculosis. Gene expression profiles generated from peripheral blood mononuclear cells isolated during past vaccine efficacy studies were analysed in two species of macaque where the outcome of infection was known. Differentially expressed genes were identified in a series of pair-wise comparisons. Post-vaccination, no genes could be identified which were indicative of a protective immune response in both species. Six weeks post-challenge, gene expression profiles generated from animals able to control TB infection revealed an up-regulation of genes related to the Th17 response whereas animals that were unable to control infection showed up-regulation of a number of iron regulatory genes. This was further investigated at post-mortem using RT-PCR to detect iron regulatory genes in conjunction with analysis of serum iron and transferrin levels. An up- regulation of genes for ferritin, transferrin receptor, SLCllAl and SLCllA2 coupled with lower serum iron levels compared with disease controllers suggests that in animals unable to control infection, iron is redirected intracellularly where it is utilised by the mycobacteria for growth. • 4 34
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available