| Summary: | Despite the progress that has been made with global control programmes, tuberculosis (TB) remains a significant challenge to health. Better diagnostics, shorter and more effective treatment regimens and improved vaccines are urgently needed. There is also increasing awareness of the need to tackle the huge burden of latent TB infection, which is estimated to affect one-third of the global population. Targeted preventative therapy is the pragmatic solution to this problem. Unfortunately, current diagnostics lack the necessary resolution to accurately identify individuals at risk of progressing to active TB disease. It has recently been proposed that TB exists on a continuous spectrum, which likely represents the dynamic interaction between the host and pathogen. Delineating this spectrum may identify individuals at risk of disease reactivation who would benefit from targeted treatment. The work presented in this thesis describes the novel use of an ex vivo whole blood functional assay to measure the capacity of individuals with active TB disease and latent infection to control mycobacterial growth. The assay identified differential functional responses that discriminated between conventional diagnostic groups, but also showed considerable overlap. Enhanced mycobacterial growth control occurred in patients with active TB disease, which may reflect a general state of immune activation. The wide range of responses seen among latently infected patients is consistent with the concept of a spectrum of infection. Characterisation of different control profiles was undertaken using a multi-platform approach. Differential gene expression was dominated by type I interferon and inflammatory signatures seen in active TB patients and some individuals with latent TB. Clustering analysis showed clear associations with functional responses. Cytokine and chemokine studies revealed strong correlations with mycobacterial growth control. Finally, increases in inflammatory monocytes, polyfunctional T cells, activated and atypical memory B cells and IgG1 responses all demonstrated correlations or associations with functional responses. These findings have potential application in developing a biosignature for TB reactivation and predictive models of risk that warrant further investigation.
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