Abstract
A major contribution to the burden of Tuberculosis (TB) comes from latent Mycobacterium tuberculosis infections (LTBI) becoming clinically active. TB and LTBI probably exist as a spectrum and currently there are no correlates available to identify individuals with LTBI most at risk of developing active disease. We set out to identify immune parameters associated with ex vivo mycobacterial growth control among individuals with active TB disease or LTBI to define the spectrum of TB infection. We used a whole blood mycobacterial growth inhibition assay to generate a functional profile of growth control among individuals with TB, LTBI or uninfected controls. We subsequently used a multi-platform approach to identify an immune signature associated with this profile. We show, for the first time, that patients with active disease had the greatest control of mycobacterial growth, whilst there was a continuum of responses among latently infected patients, likely related to the degree of immune activation in response to bacillary load. Control correlated with multiple factors including inflammatory monocytes, activated and atypical memory B cells, IgG1 responses to TB-specific antigens and serum cytokines/chemokines. Our findings offer a method to stratify subclinical TB infections and the future potential to identify individuals most at risk of progressing to active disease and benefit from chemoprophylaxis.
Highlights
A major contribution to the burden of Tuberculosis (TB) comes from latent Mycobacterium tuberculosis infections (LTBI) becoming clinically active
We present evidence supporting the concept of a heterogenous spectrum of M.tb infection, potentially an important initial step in stratifying reactivation risk in LTBI
Using a functional mycobacterial growth inhibition assays (MGIAs) we developed a continuous ordinal scale to define in vivo M.tb infection status, based on an individual’s ex vivo ability to control mycobacterial growth
Summary
A major contribution to the burden of Tuberculosis (TB) comes from latent Mycobacterium tuberculosis infections (LTBI) becoming clinically active. We set out to identify immune parameters associated with ex vivo mycobacterial growth control among individuals with active TB disease or LTBI to define the spectrum of TB infection. For the first time, that patients with active disease had the greatest control of mycobacterial growth, whilst there was a continuum of responses among latently infected patients, likely related to the degree of immune activation in response to bacillary load. Modeling estimates that even if transmission was stopped completely and instantly, reactivation from the 2 billion individuals estimated to have latent Mycobacterium tuberculosis (M.tb) infections (LTBI) would cause >100 cases per million population in 20502. A test to stratify these high-risk individuals within the latent reservoir would facilitate targeted preventative therapy, offering an alternative solution to the economic and logistic challenge of treating the global LTBI population. Gender male Place of birth UK Outside UK Ethnic group White Caucasian Sub-Saharan African Indian subcontinent Other BCG vaccinated Culture confirmed TB System Pulmonary Extrapulmonarya Miliary Completed treatment Post-treatment samples
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