Histone acetylome-wide association study of tuberculosis

Rosario, Del; Poschmann,; Kumar, Dilip; Cheng, Wood-Hi; Ong, Duu Sheng; Hajan,; Marzuki, Marzuki; Lu, Jiwen; Lee, Myeong Soo; Tang, Tang; Chee,; Lum,; Zolezzi,; Rotzschke,; Khor,; Wang, Hong; Chandy,; Libero, Gennaro De; Singhal, Amit; Prabhakar, .

doi:10.1101/644112

Cited by 2 publications

(1 citation statement)

References 55 publications

(80 reference statements)

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“…TAGAP encodes T-cell activation Rho-GTPase-activating protein, however, the exact role of TAGAP in Mtb pathogenesis is currently unknown. Several studies have linked TAGAP with active TB; TAGAP was enriched for differential acetylation peaks upon Mtb infection in granulocytes 58 and TAGAP was induced upon vaccination with AERAS-402 vaccine encoding a fusion protein of Mtb antigens. 59 Furthermore, TAGAP had higher expression in TB patients compared to LTBI and healthy controls 55 and, surprisingly, lower expression in pulmonary TB compared to household controls.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment

Doorn

Eckold

Ronacher

et al. 2022

Preprint

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Background Globally, the anti-tuberculosis (TB) treatment success rate is approximately 85%, with treatment failure, relapse and death occurring in a significant proportion of pulmonary TB patients. Treatment success is lower among people with diabetes mellitus (DM). Predicting treatment failure early after diagnosis would allow early treatment adaptation and may improve global TB control. Methods Samples were collected in a longitudinal cohort study of adult TB patients with or without concomitant DM from South Africa and Indonesia to characterize whole blood transcriptional profiles before and during anti-TB treatment, using unbiased RNA-Seq and targeted gene dcRT-MLPA. Findings We report differences in whole blood transcriptome profiles, which were observed before initiation of treatment and throughout treatment, between patients with a good versus poor anti-TB treatment outcome. An eight-gene and a 22-gene blood transcriptional signature distinguished patients with a good treatment outcome from patients with a poor treatment outcome at diagnosis (AUC=0.815) or two weeks (AUC=0.834) after initiation of anti-TB treatment, respectively. High accuracy was obtained by cross-validating this signature in an external cohort (AUC=0.749). Interpretation These findings suggest that transcriptional profiles can be used as a prognostic biomarker for treatment failure and success, even in patients with concomitant DM. Funding The research leading to these results, as part of the TANDEM Consortium, received funding from the European Community's Seventh Framework Programme (FP7/2007-2013 Grant Agreement No. 305279) and the Netherlands Organization for Scientific Research (NWO-TOP Grant Agreement No. 91214038).

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Section: Discussionmentioning

confidence: 99%

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment

Doorn

Eckold

Ronacher

et al. 2022

Preprint

View full text Add to dashboard Cite

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A 2-Dose AERAS-402 Regimen Boosts CD8+ Polyfunctionality in HIV-Negative, BCG-Vaccinated Recipients

et al. 2021

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Despite the widespread use of BCG, tuberculosis (TB) remains a global threat. Existing vaccine candidates in clinical trials are designed to replace or boost BCG which does not provide satisfying long-term protection. AERAS-402 is a replication-deficient Ad35 vaccine encoding a fusion protein of the M. tuberculosis (Mtb) antigens 85A, 85B, and TB10.4. The present phase I trial assessed the safety and immunogenicity of AERAS-402 in participants living in India – a highly TB-endemic area. Healthy male participants aged 18–45 years with a negative QuantiFERON-TB Gold in-tube test (QFT) were recruited. Enrolled participants (n=12) were randomized 2:1 to receive two intramuscular injections of either AERAS-402 (3 x 1010 viral particles [vp]); (n=8) or placebo (n=4) on study days 0 and 28. Safety and immunogenicity parameters were evaluated for up to 182 days post the second injection. Immunogenicity was assessed by a flow cytometry-based intracellular cytokine staining (ICS) assay and transcriptional profiling. The latter was examined using dual-color-Reverse-Transcriptase-Multiplex-Ligation-dependent-Probe-Amplification (dc-RT MLPA) assay. AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine-induced CD8+ T-cell responses were dominated by cells co-expressing IFN-γ, TNF-α, and IL-2 (“polyfunctional” cells) and were more robust than CD4+ T-cell responses. Five genes (CXCL10, GNLY, IFI35, IL1B and PTPRCv2) were differentially expressed between the AERAS-402-group and the placebo group, suggesting vaccine-induced responses. Further, compared to pre-vaccination, three genes (CLEC7A, PTPRCv1 and TAGAP) were consistently up-regulated following two doses of vaccination in the AERAS-402-group. No safety concerns were observed for AERAS-402 in healthy Indian adult males. The vaccine-induced predominantly polyfunctional CD8+ T cells in response to Ag85B, humoral immunity, and altered gene expression profiles in peripheral blood mononuclear cells (PBMCs) indicative of activation of various immunologically relevant biological pathways.

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Histone acetylome-wide association study of tuberculosis

Cited by 2 publications

References 55 publications

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment

Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment

A 2-Dose AERAS-402 Regimen Boosts CD8+ Polyfunctionality in HIV-Negative, BCG-Vaccinated Recipients

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