Transcriptional signatures of human peripheral blood mononuclear cells can identify the risk of tuberculosis progression from latent infection among individuals with silicosis.
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ABSTRACT: Clinical trial registration
www.clinicaltrials.gov (NCT02430259).
SUBMITTER: Ruan QL
PROVIDER: S-EPMC8354161 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mycobacterium tuberculosis (M. tuberculosis) infection in humans can cause active disease or latent infection. However, the factors contributing to the maintenance of latent infection vs. disease progression are poorly understood. In this study, we used a genome-wide RNA sequencing (RNA-seq) approach to identify host factors associated with M. tuberculosis infection status and a novel gene signature that can distinguish active disease from latent infection. By RNA-seq, we characterized transcriptional differences in purified protein derivative (PPD)-stimulated peripheral blood mononuclear cells (PBMCs) among three groups: patients with active tuberculosis (ATB), individuals with latent TB infection (LTBI), and TB-uninfected controls (CON). A total of 401 differentially expressed genes enabled grouping of individuals into three clusters. A validation study by quantitative real-time PCR (qRT-PCR) confirmed the differential expression of TNFRSF10C, IFNG, PGM5, EBF3, and A2ML1 between the ATB and LTBI groups. Additional clinical validation was performed to evaluate the diagnostic performance of these five biomarkers using 130 subjects. The 3-gene signature set of TNFRSF10C, EBF3, and A2ML1 enabled correct classification of 91.5% of individuals, with a high sensitivity of 86.2% and specificity of 94.9%. Diagnostic performance of the 3-gene signature set was validated using a clinical cohort of 147 subjects with suspected ATB. The sensitivity and specificity of the 3-gene set for ATB were 82.4 and 92.4%, respectively. In conclusion, we detected distinct gene expression patterns in PBMCs stimulated by PPD depending on the status of M. tuberculosis infection. Furthermore, we identified a 3-gene signature set that could distinguish ATB from LTBI, which may facilitate rapid diagnosis and treatment for more effective disease control.
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Project description: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.
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Project description:BACKGROUND: Humans infected with Mycobacterium tuberculosis (MTB) can delete the pathogen or otherwise become latent infection or active disease. However, the factors influencing the pathogen clearance and disease progression from latent infection are poorly understood. This study attempted to use a genome-wide transcriptome approach to identify immune factors associated with MTB infection and novel biomarkers that can distinguish active disease from latent infection. METHODOLOGY/PRINCIPAL FINDINGS: Using microarray analysis, we comprehensively determined the transcriptional difference in purified protein derivative (PPD) stimulated peripheral blood mononuclear cells (PBMCs) in 12 individuals divided into three groups: TB patients (TB), latent TB infection individuals (LTBI) and healthy controls (HC) (n?=?4 per group). A transcriptional profiling of 506 differentially expressed genes could correctly group study individuals into three clusters. Moreover, 55- and 229-transcript signatures for tuberculosis infection (TB<BI) and active disease (TB) were identified, respectively. The validation study by quantitative real-time PCR (qPCR) performed in 83 individuals confirmed the expression patterns of 81% of the microarray identified genes. Decision tree analysis indicated that three genes of CXCL10, ATP10A and TLR6 could differentiate TB from LTBI subjects. Additional validation was performed to assess the diagnostic ability of the three biomarkers within 36 subjects, which yielded a sensitivity of 71% and specificity of 89%. CONCLUSIONS/SIGNIFICANCE: The transcription profiles of PBMCs induced by PPD identified distinctive gene expression patterns associated with different infectious status and provided new insights into human immune responses to MTB. Furthermore, this study indicated that a combination of CXCL10, ATP10A and TLR6 could be used as novel biomarkers for the discrimination of TB from LTBI.
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Project description:Silicosis is a fibrotic disease caused by the inhalation of respirable silica particles, which are typically engulfed by alveolar macrophages and subsequently induce the release of inflammatory cytokines. Various animal experimental and human studies have focused on modeling silicosis, to assess the interactions of macrophages and other cell types with silica particles. There is still, however, limited knowledge on the differential response upon silica-exposure between silicosis patients and controls. We focused on studying the responsiveness of peripheral blood mononuclear cells (PBMCs) to silica nanoparticles (SiNPs) - Ludox and NM-200 - of silicosis patients and controls. The proliferative capacity of T- CD3+ and B- CD19+ cells, were evaluated via Carboxyfluorescein succinimidyl ester (CFSE) assay. The activation status of lymphocyte subsets and response to silica were also evaluated by comparing the extent of micro-granuloma or aggregate formation with the cytokine secretion profiles between both groups of individuals. The proliferative capacity of CD19+ cells was elevated in silicotic patients as opposed to controls. Subsets of regulatory T cells (CD4+ CD25+ and CD8+ CD25+) and immunoglobulins IgM and IgG were also significantly increased in patients. The number and the size of aggregates formed were higher with SiNPs stimulation in patients compared to controls. Multivariable analysis also elucidated the role of key cytokines like interleukin-1β (IL-1β), IL-6 and interferon-gamma (IFN-γ), which were upregulated in SiNP-stimulated PBMCs of patients compared to controls. Our ex vivo model thus has potential to provide insights into the immunological effects of silica particles in lymphocytes of silicosis patients and controls.
| S-EPMC9606771 | biostudies-literature
Project description:To further understand the host immune factors involved in the progression from latent tuberculosis infection (LTBI) to active tuberculosis (TB) and identify the potential signatures for discriminating TB from LTBI, the genome-wide transcriptional profile of the Mycobacterium.Tuberculosis (M.TB)–specific antigens stimulated peripheral blood mononuclear cells (PBMCs) from active TB, LTBI and health controls (HCs) were performed. A total of 209- and 234- differentially expressed genes (Fold change > 4, P < 0.05) were detected in comparisons of TB vs. LTBI and TB vs. HCs, respectively. Nineteen differentially expressed genes with top fold change between TB and the other two groups were validated in the same RNA samples by real-time PCR, and showed 94.7% consistent expression pattern with microarray test.
2018-02-14 | GSE98461 | GEO
Project description:Proteome profiling is the method of choice to identify marker proteins whose expression may be characteristic for certain diseases. The formation of such marker proteins results from disease-related pathophysiologic processes. In healthy individuals, peripheral blood mononuclear cells (PBMCs) circulate in a quiescent cell state monitoring potential immune-relevant events, but have the competence to respond quickly and efficiently in an inflammatory manner to any invasion of potential pathogens. Activation of these cells is most plausibly accompanied by characteristic proteome alterations. Therefore we investigated untreated and inflammatory activated primary human PBMCs by proteome profiling using a 'top down' 2D-PAGE approach in addition to a 'bottom up' LC-MS/MS-based shotgun approach. Furthermore, we purified primary human T-cells and monocytes and activated them separately. Comparative analysis allowed us to characterize a robust proteome signature including NAMPT and PAI2 which indicates the activation of PBMCs. The T-cell specific inflammation signature included IRF-4, GBP1 and the previously uncharacterized translation product of GBP5; the corresponding monocyte signature included PDCD5, IL1RN and IL1B. The involvement of inflammatory activated PBMCs in certain diseases as well as the responsiveness of these cells to anti-inflammatory drugs may be evaluated by quantification of these marker proteins. This article is part of a Special Issue entitled: Integrated omics.
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Project description:Despite a century of research into tuberculosis (TB), there is a dearth of reproducible, easily quantifiable, biomarkers that can predict disease onset and differentiate between host disease states. Due to the challenges associated with human sampling, nonhuman primates (NHPs) are utilized for recapitulating the closest possible modelling of human TB. To establish a predictive peripheral biomarker profile based on a larger cohort of rhesus macaques (RM), we analyzed results pertaining to peripheral blood serum chemistry and cell counts from RMs that were experimentally exposed to Mtb in our prior studies and characterized as having either developed active TB (ATB) disease or latent TB infection (LTBI). We compared lung CFU burdens and quantitative pathologies with a number of measurables in the peripheral blood. Based on our results, the investigations were then extended to the study of specific molecules and cells in the lung compartments of a subset of these animals and their immune responses. In addition to the elevated serum C-reactive protein (CRP) levels, frequently used to discern the level of Mtb infection in model systems, reduced serum albumin-to-globulin (A/G) ratios were also predictive of active TB disease. Furthermore, higher peripheral myeloid cell levels, particularly those of neutrophils, kynurenine-to-tryptophan ratio, an indicator of induced expression of the immunosuppressive molecule indoleamine dioxygenase, and an influx of myeloid cell populations could also efficiently discriminate between ATB and LTBI in experimentally infected macaques. These quantifiable correlates of disease were then used in conjunction with a regression-based analysis to predict bacterial load. Our results suggest a potential biomarker profile of TB disease in rhesus macaques, that could inform future NHP-TB research. Our results thus suggest that specific biomarkers may be developed from the myeloid subset of peripheral blood or plasma with the ability to discriminate between active and latent Mtb infection.
| S-EPMC9146669 | biostudies-literature
Project description:BackgroundAlthough the incidence of tuberculosis (TB) has dropped substantially, it still is a serious threat to human health. And in recent years, the emergence of resistant bacilli and inadequate disease control and prevention has led to a significant rise in the global TB epidemic. It is known that the cause of TB is Mycobacterium tuberculosis infection. But it is not clear why some infected patients are active while others are latent.MethodsWe analyzed the blood gene expression profiles of 69 latent TB patients and 54 active pulmonary TB patients from GEO (Transcript Expression Omnibus) database.ResultsBy applying minimal redundancy maximal relevance and incremental feature selection, we identified 24 signature genes which can predict the TB activation. The support vector machine predictor based on these 24 genes had a sensitivity of 0.907, specificity of 0.913, and accuracy of 0.911, respectively. Although they need to be validated in a large independent dataset, the biological analysis of these 24 genes showed great promise.ConclusionWe found that cytokine production was a key process during TB activation and genes like CYBB, TSPO, CD36, and STAT1 worth further investigation.
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Project description:Studies on human intraocular tuberculosis (IOTB) are extremely challenging. For understanding the pathogenesis of IOTB, it is important to investigate the mycobacterial transcriptional changes in ocular environment. Mice were challenged intravenously with Mycobacterium tuberculosis H37Rv and at 45 days post-infection, experimental IOTB was confirmed based on bacteriological and molecular assays. M. tuberculosis transcriptome was analyzed in the infected eyes using microarray technology. The identified M. tuberculosis signature genes were further validated and investigated in human IOTB samples using real-time polymerase chain reaction. Following intravenous challenge with M. tuberculosis, 45% (5/12) mice showed bacilli in the eyes with positivity for M. tuberculosis ribonucleic acid in 100% (12/12), thus confirming the paucibacillary nature of IOTB similar to human IOTB. M. tuberculosis transcriptome in these infected eyes showed significant upregulation of 12 M. tuberculosis genes and five of these transcripts (Rv0962c, Rv0984, Rv2612c, Rv0974c and Rv0971c) were also identified in human clinically confirmed cases of IOTB. Differentially expressed mycobacterial genes identified in an intravenously challenged paucibacillary mouse IOTB model and presence of these transcripts in human IOTB samples highlight the possible role of these genes for survival of M. tuberculosis in the ocular environment, thus contributing to pathogenesis of IOTB.
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