Dataset Information

The Transcriptional Signature of Active Tuberculosis Reflects Symptom Status in Extra-Pulmonary and Pulmonary Tuberculosis.

ABSTRACT:

Background

Mycobacterium tuberculosis infection is a leading cause of infectious death worldwide. Gene-expression microarray studies profiling the blood transcriptional response of tuberculosis (TB) patients have been undertaken in order to better understand the host immune response as well as to identify potential biomarkers of disease. To date most of these studies have focused on pulmonary TB patients with gene-expression profiles of extra-pulmonary TB patients yet to be compared to those of patients with pulmonary TB or sarcoidosis.

Methods

A novel cohort of patients with extra-pulmonary TB and sarcoidosis was recruited and the transcriptional response of these patients compared to those with pulmonary TB using a variety of transcriptomic approaches including testing a previously defined 380 gene meta-signature of active TB.

Results

The 380 meta-signature broadly differentiated active TB from healthy controls in this new dataset consisting of pulmonary and extra-pulmonary TB. The top 15 genes from this meta-signature had a lower sensitivity for differentiating extra-pulmonary TB from healthy controls as compared to pulmonary TB. We found the blood transcriptional responses in pulmonary and extra-pulmonary TB to be heterogeneous and to reflect the extent of symptoms of disease.

Conclusions

The transcriptional signature in extra-pulmonary TB demonstrated heterogeneity of gene expression reflective of symptom status, while the signature of pulmonary TB was distinct, based on a higher proportion of symptomatic individuals. These findings are of importance for the rational design and implementation of mRNA based TB diagnostics.

SUBMITTER: Blankley S

PROVIDER: S-EPMC5051928 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

The Transcriptional Signature of Active Tuberculosis Reflects Symptom Status in Extra-Pulmonary and Pulmonary Tuberculosis.

Blankley Simon S Graham Christine M CM Turner Jacob J Berry Matthew P R MP Bloom Chloe I CI Xu Zhaohui Z Pascual Virginia V Banchereau Jacques J Chaussabel Damien D Breen Ronan R Santis George G Blankenship Derek M DM Lipman Marc M O'Garra Anne A

PloS one 20161005 10

<h4>Background</h4>Mycobacterium tuberculosis infection is a leading cause of infectious death worldwide. Gene-expression microarray studies profiling the blood transcriptional response of tuberculosis (TB) patients have been undertaken in order to better understand the host immune response as well as to identify potential biomarkers of disease. To date most of these studies have focused on pulmonary TB patients with gene-expression profiles of extra-pulmonary TB patients yet to be compared to t ...[more]

PMID: 27706152

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Project description:To evaluate the diagnostic value of symptom screening for tuberculosis (TB) case finding defined in National Tuberculosis Control Program in China (China NTP) among elderly people(≥65 years) and younger people(<65 years).We made a secondary analysis in a population-based TB prevalence survey in China in 2010. Questionnaire including information for cough and haemoptysis was completed by face to face interview, and then chest radiography was conducted in all eligible participants. Sputum smear and culture were followed for all TB suspects. We calculated the odds ratios (OR), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the area under the receiver operating characteristic curve (AUC) of using different symptoms for screening to detect bacteriologically positive TB in subpopulations stratified by age 65, to evaluate the performance of symptom screening for TB.Of 315 newly diagnosed bacteriologically positive TB, 131 patients (41.59%) were elderly, and 48.57% of TB patients were asymptomatic. Nearly 50% patients did not present cough of any duration, and less than half present cough more than 2 weeks, a defined suspected symptom in China NTP. Cough of any duration was reported more in patients aged under 65 than those in elderly, especially for the acute cough (9.78% vs 6.87%). Those symptoms defined by China NTP were reported by less than half participants in two subpopulations. Acute cough (<2 weeks) was an independent predictor of TB in people aged under 65 (adjusted OR: 3.3, 95% CI: 2.0-5.5), but not in those aged 65 and above (adjusted OR: 1.4, 95% CI: 0.7-2.9). The specificity for each symptom was significantly higher in participants aged under 65 (P<0.01), and sensitivities of most symptoms were significantly higher among elderly (P<0.05 or P<0.01). When compared with cough for 2 weeks and more, using cough of any duration for symptom screening increased the sensitivity from 42.9% to 51. % for all participants, and the AUC increased from 0.70 to 0.74 for participants aged under 65 without significant difference.There is a high percent of asymptomatic TB patients, and those symptoms adopted in China NTP for screening is poorly predictive for TB. The presence of TB symptoms, the sensitivities and specificities of symptoms for TB were distinct between two subpopulations cut by age 65, implying different case finding strategies should be established for them. The current case finding strategy should be improved, and further studies should be done to evaluate the performance and cost-effectiveness of different symptom screening strategy.

Project description:Conventionally, facultative intracellular pathogen, Mycobacterium tuberculosis, the tuberculosis (TB) causing bacilli in human is cleared by cell-mediated immunity (CMI) with CD4(+) T cells playing instrumental role in protective immunity, while antibody-mediated immunity (AMI) is considered non-protective. This longstanding convention has been challenged with recent evidences of increased susceptibility of hosts with compromised AMI and monoclonal antibodies conferring passive protection against TB and other intracellular pathogens. Therefore, novel approaches toward vaccine development include strategies aiming at induction of humoral response along with CMI. This necessitates the identification of mycobacterial proteins with properties of immunomodulation and strong immunogenicity. In this study, we determined the immunogenic potential of M. tuberculosis Zinc metalloprotease-1 (Zmp1), a secretory protein essential for intracellular survival and pathogenesis of M. tuberculosis. We observed that Zmp1 was secreted by in vitro grown M. tuberculosis under granuloma-like stress conditions (acidic, oxidative, iron deficiency, and nutrient deprivation) and generated Th2 cytokine microenvironment upon exogenous treatment of peripheral blood mononulear cells PBMCs with recombinant Zmp1 (rZmp1). This was supported by recording specific and robust humoral response in TB patients in a cohort of 295. The anti-Zmp1 titers were significantly higher in TB patients (n = 121) as against healthy control (n = 62), household contacts (n = 89) and non-specific infection controls (n = 23). A significant observation of the study is the presence of equally high titers of anti-Zmp1 antibodies in a range of patients with high bacilli load (sputum bacilli load of 300+ per mL) to paucibacillary smear-negative pulmonary tuberculosis (PTB) cases. This clearly indicated the potential of Zmp1 to evoke an effective humoral response independent of mycobacterial load. Such mycobacterial proteins can be explored as antigen candidates for prime-boost vaccination strategies or extrapolated as markers for disease detection and progression.

Project description:BackgroundVitamin D insufficiency is common in industrialized and developing nations. Recent studies have shown that vitamin D insufficiency is associated with a higher risk of active tuberculosis. Laboratory studies provided a mechanism for this link on the basis of findings that vitamin D metabolites regulate the expression of cathelicidin (LL-37), which is an endogenous antimicrobial peptide with activity against Mycobacterium tuberculosis. Little information is available on the clinical relation between vitamin D, LL-37 concentrations, and disease severity in patients with tuberculosis.ObjectiveThe primary objective of the study was to evaluate the relation between vitamin D nutriture, serum LL-37 concentrations, and tuberculosis by using samples stored in the Tuberculosis Trials Consortium serum repository.DesignWe measured 25-hydroxyvitamin D [25(OH)D] and LL-37 concentrations in 95 serum specimens from patients with culture-confirmed pulmonary tuberculosis and correlated these concentrations to clinical and demographic variables.ResultsThe prevalence of vitamin D insufficiency [serum 25(OH)D concentration lt 30 ng/mL] in patients with active tuberculosis was 86% (n = 95) with a mean baseline serum 25(OH)D concentration of 20.4 ng/mL. Factors associated with vitamin D insufficiency were black race and indoor lifestyle. The mean ( plusmn SD) baseline LL-37 concentration was 49.5 plusmn 23.8 ng/mL. Higher LL-37 concentrations correlated with acid fast bacilli sputum smear positivity and weight gt 10% below ideal body weight. Serum vitamin D status of the study subjects did not correlate with serum LL-37 concentrations.ConclusionMore prospectively designed studies are needed to evaluate the clinical implications of vitamin D insufficiency in patients with tuberculosis and the utility of circulating LL-37 as a potential biomarker in patients with active tuberculosis disease. The parent trial was registered at clinicaltrials.gov as NCT00023335.

Dataset Information

The Transcriptional Signature of Active Tuberculosis Reflects Symptom Status in Extra-Pulmonary and Pulmonary Tuberculosis.

Background

Methods

Results

Conclusions

Publications

The Transcriptional Signature of Active Tuberculosis Reflects Symptom Status in Extra-Pulmonary and Pulmonary Tuberculosis.

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