Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response
Open Access
- 30 March 2015
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 125 (5), 1827-1838
- https://doi.org/10.1172/jci77990
Abstract
BACKGROUND. The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluation and detection of Mycobacterium tuberculosis (Mtb) in the patient’s sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that immune activation markers on Mtb-specific CD4+ T cells would be associated with Mtb load in vivo and could thus provide a gauge of Mtb infection. METHODS. Using polychromatic flow cytometry, we evaluated the expression of immune activation markers on Mtb-specific CD4+ T cells from individuals with asymptomatic latent Mtb infection (LTBI) and ATB as well as from ATB patients undergoing anti-TB treatment. RESULTS. Frequencies of Mtb-specific IFN-γ+CD4+ T cells that expressed immune activation markers CD38 and HLA-DR as well as intracellular proliferation marker Ki-67 were substantially higher in subjects with ATB compared with those with LTBI. These markers accurately classified ATB and LTBI status, with cutoff values of 18%, 60%, and 5% for CD38+IFN-γ+, HLA-DR+IFN-γ+, and Ki-67+IFN-γ+, respectively, with 100% specificity and greater than 96% sensitivity. These markers also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment. CONCLUSION. We have identified host blood-based biomarkers on Mtb-specific CD4+ T cells that discriminate between ATB and LTBI and provide a set of tools for monitoring treatment response and cure. TRIAL REGISTRATION. Registration is not required for observational studies. FUNDING. This study was funded by Emory University, the NIH, and the Yerkes National Primate Center.This publication has 51 references indexed in Scilit:
- Transcriptional Blood Signatures Distinguish Pulmonary Tuberculosis, Pulmonary Sarcoidosis, Pneumonias and Lung CancersPLOS ONE, 2013
- Mycobacterium tuberculosis‐specific CD8+ T cells are functionally and phenotypically different between latent infection and active diseaseEuropean Journal of Immunology, 2013
- CD8+T Cells Provide an Immunologic Signature of Tuberculosis in Young ChildrenAmerican Journal of Respiratory and Critical Care Medicine, 2012
- Role of the Clinical Mycobacteriology Laboratory in Diagnosis and Management of Tuberculosis in Low-Prevalence SettingsJournal of Clinical Microbiology, 2011
- Partial recessive IFN-γR1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindredsHuman Molecular Genetics, 2011
- An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosisNature, 2010
- Shortening Treatment in Adults with Noncavitary Tuberculosis and 2-Month Culture ConversionAmerican Journal of Respiratory and Critical Care Medicine, 2009
- Analysis of Mycobacterium tuberculosis-Specific CD8 T-Cells in Patients with Active Tuberculosis and in Individuals with Latent InfectionPLOS ONE, 2009
- Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infectionThe Journal of Experimental Medicine, 2008
- Loss of Receptor on Tuberculin-Reactive T-Cells Marks Active Pulmonary TuberculosisPLOS ONE, 2007