Ontology highlight
ABSTRACT:
PROVIDER: PRJNA741102 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15014600_1.fastq.gz | Fastqsanger.gz | |||
| SRR15014600_2.fastq.gz | Fastqsanger.gz | |||
| SRR15014700_1.fastq.gz | Fastqsanger.gz | |||
| SRR15014700_2.fastq.gz | Fastqsanger.gz | |||
| SRR15014601_1.fastq.gz | Fastqsanger.gz |
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Project description:Global control of the tuberculosis (TB) epidemic is seriously threatened by increasing prevalence of drug resistant (DR) M. tuberculosis (MTB) isolates. Many genome-wide studies have identified DR-associated SNPs and investigated their role in DR mechanisms. However, DR in ~30% of isolates has no clear genetic basis. DR mechanisms related to variation in gene/protein expression are known, but not well-studied.
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Project description:Background. Diabetes mellitus (DM) increases tuberculosis (TB) severity. We previously reported baseline blood microarray data in a South Indian pulmonary TB cohort with or without DM, finding no qualitative or quantitative differences in immune pathway gene expression. To extend those observations, we compared baseline and longitudinal blood gene expression in TB patients from South India and Brazil. Methods. Adults with pulmonary TB, with or without DM, were enrolled at two sites in India and one site in Brazil. Blood RNA sequencing (RNAseq) was performed at baseline and treatment months 2 and 6. Differentially expressed genes (DEGs) and pathway activation were compared by group and site. Comparison was also made with published RNAseq data from the TANDEM study South African and Romanian cohorts. Findings. No consistent pattern of DEGs discriminated TB from TBDM in India or Brazil. Pathway analysis also showed little commonality between sites, although a shared profile of complement activation and matrix degradation was identified in TBDM. Indian participants showed marked longitudinal changes in DEGs and pathways at 2 and 6 months of treatment, whereas these were stable in Brazilian participants. High variability in gene expression was observed between sites at baseline and during treatment. Interpretation. DM exacerbates matrix degradation in TB but is not associated with major immune gene expression or pathway differences compared to TB without DM. Comparison between cohorts in India, Brazil, Romania, and South Africa revealed an unexpectedly high degree of site-specific variation that may reflect population differences in TB pathobiology.
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Project description:Tuberculosis (TB) remains a deadly disease. The genetic diversity of Mycobacterium tuberculosis was neglected in the past, but is increasingly recognized as a determinant of immune responses and clinical outcomes of TB. However, how this bacterial diversity orchestrates immune responses to direct differences in TB severity remains unknown. We studied 681 patients with pulmonary TB and found that phylogenetically related M. tuberculosis isolates from cases with mild disease induced robust cytokine responses in macrophages. In contrast, isolates associated with severe TB cases failed to do so. Using representative isolates, we show that M. tuberculosis inducing a low cytokine response in macrophages also diminished activation of cytosolic surveillance systems, including cGAS and the inflammasome, suggesting a novel mechanism of immune escape. Isolates exhibiting this evasion strategy carried mutations in various components of the ESX-I secretion system. We conclude that host interactions with different M. tuberculosis strains results in variable TB severity.
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Project description:72 candidate biomarkers evaluated for TB diagnosis using mRNA purified from whole blood of Active TB patients recruited in the UK and India, LTB and two groups of controls from the UK (i) from a low incidence region and (ii) individuals variably domiciled in the UK and India. Tuberculosis (TB) remains a major global threat and diagnosis of active TB ((ATB) both extra-pulmonary (EPTB) and pulmonary (PTB)) and latent TB (LTBI) remains challenging, particularly in high-burden countries which still rely heavily on conventional methods. Although molecular diagnostic methods are available, e.g., Cepheid GeneXpert, they are not universally available in all high TB burden countries. There is intense focus on immune biomarkers for use in TB diagnosis, which could provide alternative low-cost, rapid diagnostic solutions. In our previous gene expression studies, we identified peripheral blood leukocyte (PBL) mRNA biomarkers in a non-human primate TB aerosol-challenge model. Here, we describe a study to further validate select mRNA biomarkers from this prior study in new cohorts of patients and controls, as a prerequisite for further development. PBL mRNA was purified from ATB patients recruited in the UK and India, LTBI and two groups of controls from the UK (i) a low TB incidence region (CNTRLA) and (ii) individuals variably-domiciled in the UK and Asia ((CNTRLB), the latter TB high incidence regions). Seventy-two mRNA biomarker gene targets were analyzed by qPCR using the Roche Lightcycler 480 qPCR platform and data analyzed using GeneSpring™ 14.9 bioinformatics software. Differential expression of fifty-three biomarkers was confirmed between MTB infected, LTBI groups and controls, seventeen of which were significant using analysis of variance (ANOVA): CALCOCO2, CD52, GBP1, GBP2, GBP5, HLA-B, IFIT3, IFITM3, IRF1, LOC400759 (GBP1P1), NCF1C, PF4V1, SAMD9L, S100A11, TAF10, TAPBP, and TRIM25. These were analyzed using receiver operating characteristic (ROC) curve analysis. Single biomarkers and biomarker combinations were further assessed using simple arithmetic algorithms. Minimal combination biomarker panels were delineated for primary diagnosis of ATB (both PTB and EPTB), LTBI and identifying LTBI individuals at high risk of progression which showed good performance characteristics. These were assessed for suitability for progression against the standards for new Tuberculosis diagnostic tests delineated in the published World Health Organization (WHO) technology product profiles (TPPs)
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Project description:Background Pediatric tuberculosis (TB) diagnosis is often challenging due to difficultly obtaining diagnostic respiratory specimens, which may contain low concentrations of Mycobacterium tuberculosis (Mtb) bacilli. However, we have reported that an immuno-affinity liquid chromatography-tandem mass spectrometry TB assay (ILM-TB) that detects a peptide derived from Mtb 10-kDa culture filtrate protein (CFP10pep) can diagnose TB regardless of patient age or infection site when analyzing trypsin-digested blood samples.
Methods Discovery and validation cohorts were respectively generated from children who consecutively presented at two hospitals in South Africa (SA) from April 2012 to August 2017 (157 children <13 years-of-age) or at two communities in the Dominican Republic (DR) from July 2019 to May 2023 (101 children <17 years-of-age). All children were evaluated for TB at enrollment and 6-months post-enrollment, and assigned confirmed, unconfirmed, or unlikely TB diagnoses based on the 2015 NIH criteria for pediatric TB. Serum samples were collected at and two and six months after SA/DR enrollment, and at two weeks DR post-enrollment (270 SA and 304 DR samples) to evaluate ILM-TB assay performance.
Findings SA and DR serum ILM-TB results had comparable sensitivity (82·9% and 84·4%) to respiratory culture and Xpert for confirmed TB, and robust sensitivity (80·5% and 76·5%) for unconfirmed TB, with differential specificity for unlikely TB cases with and without TB consistent symptoms (78·4–98·1%). CFP10pep levels decreased by six months post-treatment initiation only in children with positive treatment responses.
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