Abstract
To better understand the host immune response involved in the progression from latent tuberculosis infection (LTBI) to active tuberculosis (TB) and identify the potential signatures for discriminating TB from LTBI, we performed a genome-wide transcriptional profile of Mycobacterium tuberculosis (M.TB)–specific antigens-stimulated peripheral blood mononuclear cells (PBMCs) from patients with TB, LTBI individuals and healthy controls (HCs). A total of 209 and 234 differentially expressed genes were detected in TB vs. LTBI and TB vs. HCs, respectively. Nineteen differentially expressed genes with top fold change between TB and the other 2 groups were validated using quantitative real-time PCR (qPCR), and showed 94.7% consistent expression pattern with microarray test. Six genes were selected for further validation in an independent sample set of 230 samples. Expression of the resistin (RETN) and kallikrein 1 (KLK1) genes showed the greatest difference between the TB and LTBI or HC groups (P < 0.0001). Receiver operating characteristic curve (ROC) analysis showed that the areas under the curve (AUC) for RETN and KLK1 were 0.844 (0.783–0.904) and 0.833 (0.769–0.897), respectively, when discriminating TB from LTBI. The combination of these two genes achieved the best discriminative capacity [AUC = 0.916 (0.872–0.961)], with a sensitivity of 71.2% (58.7%–81.7%) and a specificity of 93.6% (85.7%–97.9%). Our results provide a new potentially diagnostic signature for discriminating TB and LTBI and have important implications for better understanding the pathogenesis involved in the transition from latent infection to TB activation.
Highlights
Great effort has been made to improve the diagnosis and treatment of tuberculosis (TB), mortality and morbidity remains high, with more than 9.0 million new cases and more than 1.5 million deaths worldwide each year [1,2,3]
Identifying the immunologic parameters involved in active TB will help improve early diagnosis and facilitate our understanding of the pathogenesis involved in the transition of latent infection to TB activation
Microarray techniques were applied to compare the transcriptional profiles of active TB patients, latent tuberculosis infection (LTBI) and healthy controls (HCs) individuals
Summary
Great effort has been made to improve the diagnosis and treatment of tuberculosis (TB), mortality and morbidity remains high, with more than 9.0 million new cases and more than 1.5 million deaths worldwide each year [1,2,3]. Mycobacterium tuberculosis (M.TB) infection generally remains asymptomatic as a so called latent tuberculosis infection (LTBI). It will reactivate to active TB (5–15%) when individuals are co-infected with HIV, are using immunosuppressive drugs, have diabetes mellitus and/or a compromised immune system [4,5,6,7]. Host-pathogen interactions determine the outcome of M.TB infection, the immunological factors involved in the host immune response network in M.TB infection and LTBI reactivation have not yet been clearly elucidated. There is has not been a useful method for discriminating active TB from LTBI. Current interferon-γ release assays (IGRAs) that detect IFN-γ release from T cells in response to 2 www.impactjournals.com/oncotarget
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