An RNA-seq Based Machine Learning Approach Identifies Latent Tuberculosis Patients With an Active Tuberculosis Profile

Estévez, Olivia; Anibarro, Luis; Garet, Elina; Pallarés, Ángeles; Barcia, Laura; Calviño, Laura; Maueia, Cremildo; Mussá, Tufária; Fdez-Riverola, Florentino; Glez-Peña, Daniel; Reboiro-Jato, Miguel; López-Fernández, Hugo; Fonseca, Nuno A.; Reljić, Rajko; González-Fernández, África

doi:10.3389/fimmu.2020.01470

Cited by 29 publications

(27 citation statements)

References 38 publications

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“…Here we reported increased expression of immunoglobulin and plasma cell transcripts in FDG-avid relative to non-avid tissues from patients with sputum culture-negative tuberculosis. This finding is consistent with a recent study of patients with latent tuberculosis in which two patient clusters were identified: the cluster predicted as infected with tuberculosis had higher expressions of 41 immunoglobulin and 2 plasma cell transcripts than the cluster predicted as uninfected (7).…”

Section: Discussionsupporting

confidence: 92%

Immune deposit and vasculopathy in metabolic-active lung tissues of patients with pulmonary tuberculosis

Wang

Wen

et al. 2021

Preprint

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Metabolic activity in pulmonary lesion is associated with disease severity and relapse risk in tuberculosis. However, the nature of the metabolic activity associated with tuberculosis in humans remains unclear. Previous works indicate that tuberculosis bears resemblance transcriptionally with systemic lupus erythematosus in peripheral blood, except that the plasma cell component was absent in tuberculosis. Here we reported that the missing transcriptional component was present within the metabolic active tissues in the lung of patients with sputum culture-negative tuberculosis, within which increased levels of circulating immune complexes and anti-dsDNA antibodies were found relative to nearby non-metabolic active tissues. Histological examination revealed specific vascular deposition of immune complexes, neutrophil extracellular traps, and vascular necrosis in the metabolic-active tissue. Thus, tuberculosis-initiated metabolic activity was associated with hyperactive antibody responses and vascular pathology, and shared features with systemic lupus erythematosus and other autoimmune diseases. We discussed these observations in the context of earlier literatures demonstrating that similar effects could be induced in humans and animal models by complete freund’s adjuvant, the most potent antibody response inducer ever reported. Our small case series, if verified in a larger size study, might help inform host-directed therapies to alleviate disease progression and augment treatment efficacy.

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Section: Discussionsupporting

confidence: 92%

Immune deposit and vasculopathy in metabolic-active lung tissues of patients with pulmonary tuberculosis

Wang

Wen

et al. 2021

Preprint

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“…After demonstrating that the LTBI and NTB groups had distinct DNA methylation traits, knowing that heterogenicity of the epigenome of LTBI subjects has previously been demonstrated 48 and that LTBI can be viewed as a spectrum 22 , we performed a heatmap analysis based on the top DMCs of the DNA methylation analysis (265 DMCs, p -value BH <0.05, log 2 fold change ≥|0.3|) that showed that the LTBI group, with the exception of one participant, clustered into one group (Fig. 3a).…”

Section: Resultsmentioning

confidence: 99%

“…In order to investigate whether we could identify any TB-like subjects within the diverse LTBI group, as previously demonstrated by Estévez et al . 48 , we recruited two individuals with TB and with ongoing treatment to the study (Table 2). The cluster analysis revealed that the DRTB group clustered with the 5 LTBI subjects (Fig.…”

Section: Resultsmentioning

confidence: 99%

DNA methylomes derived from alveolar macrophages display distinct patterns in latent tuberculosis - implication for interferon gamma release assay status determination

Pehrson¹,

Das²,

N³

et al. 2021

Preprint

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Host innate immune cells, including alveolar macrophages, have been identified as key players in the early eradication of Mycobacterium tuberculosis and in the maintenance of an anti-mycobacterial immune memory, which is believed to be induced through epigenetic changes. The aim of the study was to elucidate whether exposure to M. tuberculosis induced a different DNA methylation pattern of alveolar macrophages and pulmonary T lymphocytes. Alveolar macrophages and T lymphocytes were isolated from induced sputum obtained from individuals living in Lima, which is an area high endemic for tuberculosis. To determine the latent tuberculosis infection status of the subjects, an interferon-γ release assay was performed. We evaluated the DNA methylomes of the alveolar macrophages and T lymphocytes using the Illumina Infinium Human Methylation 450K Bead Chip array, revealing a distinct DNA methylation pattern in alveolar macrophages allowing the discrimination of asymptomatic individuals with latent tuberculosis infection from non-infected individuals. Pathway analysis revealed that cell signalling of inflammation and chemokines in alveolar macrophages play a role in latent tuberculosis infection. In conclusion, we demonstrated that DNA methylation in alveolar macrophages can be used to determine the tuberculosis infection status of individuals in a high endemic setting.

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“…The same group then went on to identify panels which could distinguish pulmonary TB, pulmonary sarcoidosis, pneumonia and lung cancer ( 114 ). This field of research has subsequently become a focus of intense interest and these and a number of other groups have identified various discriminatory signatures for the various forms and stages of TB; ATB, EPTB, LTBI and incipient TB and also for exposure in household contacts, risk of progression to active disease and response to therapy ( 82 , 96 , 108 – 113 , 115 – 136 ). Some of these have subsequently been reviewed or further validated in comparative cohort studies by other workers in the field ( 88 – 90 , 110 , 126 , 136 – 139 ).…”

Section: Introductionmentioning

confidence: 99%

“…This field of research has subsequently become a focus of intense interest and these and a number of other groups have identified various discriminatory signatures for the various forms and stages of TB; ATB, EPTB, LTBI and incipient TB and also for exposure in household contacts, risk of progression to active disease and response to therapy ( 82 , 96 , 108 – 113 , 115 – 136 ). Some of these have subsequently been reviewed or further validated in comparative cohort studies by other workers in the field ( 88 – 90 , 110 , 126 , 136 – 139 ). Of the previously published blood transcriptional biomarker panels for active pulmonary tuberculosis reviewed recently by Turner et al ( 137 ), four panels achieved the highest diagnostic accuracy and two met the minimum but not optimum WHO target product profiles (TPP) requirements for a triage test ( 74 , 140 ); Sweeney et al [Sweeney3 ( 120 )], Roe et al [Roe3 and BATF2 ( 119 , 121 )] ( 78 ) and Kaforou et al [Kaforou25 ( 132 )].…”

Section: Introductionmentioning

confidence: 99%

Validation of Differentially Expressed Immune Biomarkers in Latent and Active Tuberculosis by Real-Time PCR

et al. 2021

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Tuberculosis (TB) remains a major global threat and diagnosis of active TB ((ATB) both extra-pulmonary (EPTB), pulmonary (PTB)) and latent TB (LTBI) infection 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. Whole blood 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 TB diagnostic tests delineated in the published World Health Organization (WHO) technology product profiles (TPPs).

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An RNA-seq Based Machine Learning Approach Identifies Latent Tuberculosis Patients With an Active Tuberculosis Profile

Cited by 29 publications

References 38 publications

Immune deposit and vasculopathy in metabolic-active lung tissues of patients with pulmonary tuberculosis

Immune deposit and vasculopathy in metabolic-active lung tissues of patients with pulmonary tuberculosis

DNA methylomes derived from alveolar macrophages display distinct patterns in latent tuberculosis - implication for interferon gamma release assay status determination

Validation of Differentially Expressed Immune Biomarkers in Latent and Active Tuberculosis by Real-Time PCR

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