Abstract
Determining what constitutes protective immunity to TB is critical for the development of improved diagnostics and vaccines. The comparison of the immune system between contacts of TB patients, who later develop TB disease (progressors), versus contacts who remain healthy (non-progressors), allows for identification of predictive markers of TB disease. This study provides the first comprehensive analysis of the immune system of progressors and non-progressors using a well-characterised TB case-contact (TBCC) platform in The Gambia, West Africa. 22 progressors and 31 non-progressors were analysed at recruitment, 3 months and 18 months (time to progression: median[IQR] of 507[187–714] days). Immunophenotyping of PBMC, plasma cytokine levels and RT-MLPA analysis of whole blood-derived RNA was performed to capture key immune system parameters. At recruitment, progressors had lower PBMC proportions of CD4+ T cells, NKT cells and B cells relative to non-progressors. Analysis of the plasma showed higher levels of IL-18 in progressors compared to non-progressors and analysis of the RNA showed significantly lower gene expression of Bcl2 but higher CCR7 in progressors compared to non-progressors. This study shows several markers that may predict the onset of active TB at a very early stage after infection. Once these markers have been validated in larger studies, they provide avenues to prospectively identify people at risk of developing TB, a key issue in the testing of new TB vaccines.
Highlights
Close to one-third of the world’s population is infected with Mycobacterium tuberculosis (MTb), the causative agent of tuberculosis (TB), with infection rates highest in poverty-stricken countries in Africa and Asia [1]
One such study in The Gambia followed 2348 contacts of TB cases for 2 years resulting in 26 progressors of which half were positive by TST at recruitment and half were positive by ELISPOT [10]
This study provides the first detailed comparison of the immune system between contacts of TB cases who progress to active disease and those who don’t progress, increasing our knowledge of what constitutes protective immunity in TB
Summary
Close to one-third of the world’s population is infected with Mycobacterium tuberculosis (MTb), the causative agent of tuberculosis (TB), with infection rates highest in poverty-stricken countries in Africa and Asia [1]. The majority of TB biomarker studies to date have focused on differences between subjects with active TB compared to latently infected counterparts [2,3,4,5] These have shown the unequivocal role of CD4+ T cells and IFN-c production in TB immunity [2,3,4,5], yet do not allow distinction between the underlying cause of progression to active TB and the dynamics of immune changes leading to or resulting from this progression. More complex immunological parameters need to be assessed in order to determine more sensitive bio-signatures of protection or susceptibility This will aid in development of effective TB vaccines but will reduce TB transmission rates by enabling identification and earlytreatment of susceptible individuals
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