RePORT: C-TRIUMPH: Biomarkers for Tuberculosis Diagnosis and Treatment Response

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To develop non-sputum, blood-based tools for TB diagnosis and treatment, we urgently need biomarkers that identify active TB (ATB) cases and accurately distinguish them from latent TB infection (LTBI). Such biomarkers, when validated in diverse populations, can be developed into improved tests for TB and as surrogate markers of treatment response and success. They may also serve as predictive biomarkers of TB progression from LTBI, including in vaccine efficacy trials.
We recently identified host biomarkers on patients’ antigen-specific T cells that accurately identify pulmonary ATB. These markers accurately classified ATB and LTBI in HIV-uninfected adults with 100% specificity and >96% sensitivity and correlated with decreasing mycobacterial loads during treatment. To further validate these biomarkers, it is important to evaluate their performance in identifying TB across a broader spectrum of Mtb infection in high-burden settings. In collaboration with RePORT-India investigators, we propose to expand our studies using cryopreserved peripheral blood mononuclear cells (PBMC) from the CTRIUMPh biorepository. We will select specimens that represent a wide range of treatment-naïve adult and pediatric ATB cases in both HIV-infected and HIV-uninfected individuals, asymptomatic contacts of TB index cases to evaluate the performance of our candidate biomarkers in diagnosing TB by flow cytometry. We will also include ATB patients on anti-TB treatment to evaluate response to treatment. 
Aim 1: To evaluate biomarker performance on PBMCs from confirmed pulmonary TB and difficult-to-diagnose cases such as sputum smear-negative and HIV-infected individuals, extrapulmonary and pediatric TB patients. 
Aim 2: To assess the ability of our biomarkers to monitor treatment response by selecting PBMCs from a subset of adult ATB patients, obtained at Time 0 (pre-treatment) and 1, 2, 6, and 12 after treatment initiation.
Aim 3: To use comprehensive immune profiling by mass cytometry (CyTOF) and multiparameter flow cytometry on a subset of ATB and control samples, to generate antigen-specific signatures of Adult TB, with the goal of discovering new markers that could further increase the sensitivity of our candidate biomarkers, particularly for difficult-to diagnose TB cases.

Emory University School of Medicine, Atlanta, GA