Identifying correlates of risk for future tuberculosis disease progression in children (INTREPID)

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PROJECT SUMMARY Background: Seventy million children globally are estimated to be infected with Mycobacterium tuberculosis (Mtb), the bacteria which causes tuberculosis (TB). Of these, 1 million develop TB disease each year with a quarter of them dying. Young children and those living with HIV are at high risk of progressing from Mtb infection to TB disease and of developing severe forms of TB. They therefore represent a key population to target with TB preventive therapy (TPT). Providing TPT to all children exposed to TB, especially in settings with high TB burden, results in substantial overtreatment, with associated costs and toxicity. Yet the current tests of Mtb infection are inadequate to predict future progression to disease in children. Developing new tests that accurately predict which TB-exposed children will progress to TB, is a critical priority and will allow for more targeted approaches to TB prevention. The identification of Mtb biomarkers in children should also consider relevant other factors, including age, and exposure to other common pathogens. Several common viruses have been shown to influence the risk of developing TB and are likely to affect biomarker signatures, yet few studies have evaluated the influence of viruses on childhood TB biomarkers. Finally, current tests of Mtb infection indicate immunological sensitization to Mtb rather than viable bacilli. If it were possible to identify a biosignature associated with Mtb death, this could provide an additional strategy for targeted TPT approaches in young children. Our group has an extensive track record of translational clinical research into pediatric TB. Our team consists of world leaders in the fields of clinical pediatrics, epidemiology, immunology, proteomics, transcriptomics, and bioinformatics. Methods: We will use samples from our three rigorously conducted studies in children <5 years, a drug-resistant TB preventive therapy trial, an observational household contact study, and a prospective diagnostic study, all conducted in a setting with high burden of TB and HIV. We will carry out a cross-sectional analysis to explore differences in biosignatures along the TB disease spectrum, nested case-control studies in longitudinal cohorts to evaluate risks of progression to Mtb infection and TB disease, and studies to evaluate changes in signatures on treatment for Mtb infection and early disease. We will use proteomic (SomaScan), transcriptomic (RNA-seq), metabolomic (mass spectrometry) and antibody (Systems Serology) approaches, and use a training/test design, to identify biomarker signatures. We will examine biosignatures in the context of clinical co-variates and viral exposure (PepSeq and RNA-seq). Finally, we will integrate the different approaches to generate the most robust biomarker combinations and provide the most granular insight into the biology of TB disease progression. Impact: Identifying novel biomarkers of TB disease progression in young children, including those living with HIV, would transform the global response to pediatric TB. For the first time, it would be possible to prevent TB by identifying and effectively treating children at the highest risk of future disease. This would have a substantial impact on overall morbidity and mortality.