Epigenetics and Proteomics Join Transcriptomics in the Quest for Tuberculosis Biomarkers

Esterhuyse, Maria M.; Weiner, January; Caron, Étienne; Loxton, André G.; Iannaccone, Marco; Wagman, Chandre; Saikali, Philippe; Stanley, Kim; Wolski, Witold; Mollenkopf, Hans-Joachim; Schick, Matthias; Aebersold, Ruedi; Linhart, Heinz; Walzl, Gerhard; Kaufmann, Stefan H. E.

doi:10.1128/mbio.01187-15

Cited by 71 publications

(64 citation statements)

References 39 publications

(53 reference statements)

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“…Correspondingly, prominent gene expression regulation has been found in blood cells of patients with pulmonary TB or LTBI (Berry et al, 2010; Lu et al, 2011; Maertzdorf et al, 2011, 2012; Bloom et al, 2013; Anderson et al, 2014; Esterhuyse et al, 2015; Laux da Costa et al, 2015; Zak et al, 2016). The potential applications of biomarkers for TB include not only the improvement of the current diagnostic tests, but also the possibility of assessing the response to drug therapy and targeted screening of eligible subjects for new TB vaccines and therapeutic trials.…”

Section: Introductionmentioning

confidence: 97%

Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood

et al. 2016

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Lately, much effort has been made to find mRNA biomarkers for tuberculosis (TB) disease/infection with microarray-based approaches. In a pilot investigation, through RNA sequencing technology, we observed a prominent modulation of DOCK9, EPHA4, and NPC2 mRNA abundance in the blood of TB patients. To corroborate these findings, independent validations were performed in cohorts from different areas. Gene expression levels in blood were evaluated by quantitative real-time PCR (Brazil, n = 129) or reanalysis of public microarray data (UK: n = 96; South Africa: n = 51; Germany: n = 26; and UK/France: n = 63). In the Brazilian cohort, significant modulation of all target-genes was observed comparing TB vs. healthy recent close TB contacts (rCt). With a 92% specificity, NPC2 mRNA high expression (NPC2high) showed the highest sensitivity (85%, 95% CI 65%–96%; area under the ROC curve [AUROC] = 0.88), followed by EPHA4 (53%, 95% CI 33%–73%, AUROC = 0.73) and DOCK9 (19%, 95% CI 7%–40%; AUROC = 0.66). All the other reanalyzed cohorts corroborated the potential of NPC2high as a biomarker for TB (sensitivity: 82–100%; specificity: 94–97%). An NPC2high profile was also observed in 60% (29/48) of the tuberculin skin test positive rCt, and additional follow-up evaluation revealed changes in the expression levels of NPC2 during the different stages of Mycobacterium tuberculosis infection, suggesting that further studies are needed to evaluate modulation of this gene during latent TB and/or progression to active disease. Considering its high specificity, our data indicate, for the first time, that NPC2high might serve as an accurate single-gene biomarker for TB.

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Section: Introductionmentioning

confidence: 97%

Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood

et al. 2016

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“…Technical advances in high-throughput techniques now facilitate the investigation of genetic, epigenetic and proteomic signatures of tuberculosis 82 . A recent study prospectively evaluated 6363 SA adolescents with LTBI to identify gene signatures predicting progression to active tuberculosis 83 .…”

Section: Gene Expression Profilesmentioning

confidence: 99%

Tuberculosis—advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers

Wallis¹,

Maeurer²,

Mwaba³

et al. 2016

The Lancet Infectious Diseases

240

173

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Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 million deaths reported in 2014. WHO estimates 480,000 cases of these were multidrug resistant (MDR). Less than half of patients who entered into treatment for MDR tuberculosis successfully completed that treatment, mainly due to high mortality and loss to follow-up. These in turn illustrate weaknesses in current treatment regimens and national tuberculosis programmes, coupled with operational treatment challenges. In this Review we provide an update on recent developments in the tuberculosis drug-development pipeline (including new and repurposed antimicrobials and host-directed drugs) as they are applied to new regimens to shorten and improve outcomes of tuberculosis treatment. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR tuberculosis, and two new antimicrobial drug candidates are in early-stage trials. Several trials to reduce the duration of therapy in MDR and drug-susceptible tuberculosis are ongoing. A wide range of candidate host-directed therapies are being developed to accelerate eradication of infection, prevent new drug resistance, and prevent permanent lung injury. As these drugs have been approved for other clinical indications, they are now ready for repurposing for tuberculosis in phase 2 clinical trials. We assess risks associated with evaluation of new treatment regimens, and highlight opportunities to advance tuberculosis research generally through regulatory innovation in MDR tuberculosis. Progress in tuberculosis-specific biomarkers (including culture conversion, PET and CT imaging, and gene expression profiles) can support this innovation. Several global initiatives now provide unique opportunities to tackle the tuberculosis epidemic through collaborative partnerships between high-income countries and middle-income and low-income countries for clinical trials training and research, allowing funders to coordinate several national and regional programmes for greatest overall effect.

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“…One issue not addressed in previous HAWAS studies [14][15][16] is reproducibility of DA signals. First, we inspected a cluster of DA peaks detected in both granulocytes and monocytes from the discovery cohort near the Guanylate Binding Protein (GBP) genes, whose expression has previously been associated with TB susceptibility and host response 10,18 . Almost all of these peaks were also detected as DA in the validation cohort ( Fig.…”

Section: (Ihec;mentioning

confidence: 99%

Histone acetylome-wide association study of tuberculosis

Rosario

Poschmann

Kumar

et al. 2019

Preprint

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Host-cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here, we describe the first histone acetylome-wide association study (HAWAS) of an infectious disease, based on genome-wide H3K27 acetylation profiling of peripheral granulocytes and monocytes from subjects with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Chinese discovery cohort, which were validated in a subsequent multi-ethnic cohort, thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression in a third cohort. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulated Akt-mTOR signaling and promoted Mtb clearance in vitro. We performed histone acetylation QTL analysis on the dataset and identified candidate causal variants for immune phenotypes. Our study serves as proof-ofprinciple for HAWAS to infer mechanisms of host response to pathogens.

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Epigenetics and Proteomics Join Transcriptomics in the Quest for Tuberculosis Biomarkers

Cited by 71 publications

References 39 publications

Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood

Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood

Tuberculosis—advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers

Histone acetylome-wide association study of tuberculosis

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