Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1047645 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27020609_1.fastq.gz | Fastqsanger.gz | |||
| SRR27020609_2.fastq.gz | Fastqsanger.gz | |||
| SRR27020610_1.fastq.gz | Fastqsanger.gz | |||
| SRR27020610_2.fastq.gz | Fastqsanger.gz | |||
| SRR27020611_1.fastq.gz | Fastqsanger.gz |
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Project description:In view of emerging drug-resistant tuberculosis, host directed therapies are urgently needed to improve treatment outcomes with currently available anti-tuberculosis therapies. One option is to interfere with the formation of lipid-laden “foamy” macrophages in the infected host. Here, we provide evidence that WNT6, a member of the evolutionary conserved WNT signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase-2 (ACC2) during pulmonary TB. In addition, we demonstrate that Mycobacterium tuberculosis (Mtb) facilitates its intracellular growth and dissemination in the host by exploiting the WNT6-ACC2 pathway. Using genetic and pharmacological approaches, we show that lack of functional WNT6 or ACC2 significantly reduces intracellular TAG levels, Mtb growth and necrotic cell death of macrophages. In combination with the anti-TB drug isoniazid, pharmacological inhibition of ACC2 improved anti-mycobacterial treatment in vitro and in vivo. Therefore, we propose the WNT6-ACC2 signaling pathway as a promising target for a host-directed therapy to reduce intracellular replication of Mtb by modulating neutral lipid metabolism.
2021-06-01 | GSE160039 | GEO
Project description:Drug-resistant tuberculosis remains a major global health challenge, and excessive inflammation may contribute to tissue damage and poor outcomes. We conducted a phase IIA prospective open-label pilot trial (ClinicalTrials.gov: NCT02781909) evaluating adjunctive ibuprofen in adults with pulmonary pre-extensively drug-resistant (pre-XDR) or extensively drug-resistant (XDR) tuberculosis in Georgia. Twenty-eight participants received individualized background anti-tuberculosis regimens alone (n = 14) or with ibuprofen 400 mg daily for 2 months (n = 14) and were followed for 6 months. The primary efficacy outcome was the proportion of participants showing clinical and/or microbiological benefit, assessed by sputum culture conversion, radiological evolution, and WHO-defined treatment outcomes. Secondary outcomes were safety and tolerability, health-related quality of life, and inflammatory and transcriptomic responses. Adding adjunctive ibuprofen did not improve month-2 sputum culture negativity, time to stable culture conversion, radiological evolution, or final treatment outcomes. Safety and tolerability were similar between groups. Adverse events were recorded and reviewed, but not formally graded for severity. Ibuprofen treatment was associated with numerically greater reductions in several blood-based inflammatory measures and in transcriptomic signature scores associated with poor tuberculosis outcomes. These findings are exploratory and do not demonstrate clinical benefit but indicate biological activity and support evaluation of anti-inflammatory host-directed therapies in larger controlled trials.
2026-05-21 | GSE298762 | GEO
Project description:We investigated candidate host-directed therapies for tuberculosis in vitro. BMDMs from tuberculosis susceptible mice B6.Sst1S were stimulated with TNF and infected with Mtb. The infected macrophage were treated with Rocaglamide A, ISRIB and JNK inhibitor SP600125 alone or in combinations to asses the inhibitors' effectas on macrophage transcriptome.
2023-10-04 | GSE237582 | GEO
Project description:<p>Drug-resistant tuberculosis (TB) remains a major global health challenge. Host-directed therapies (HDTs) aim to limit tissue damage, shorten treatment, and improve outcomes by modulating immune responses. We evaluated the safety and potential efficacy of adjunctive ibuprofen an inexpensive, well-tolerated non-steroidal anti-inflammatory drug in pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR)TB. In this prospective, open-label, randomized pilot study (NCT02781909) in Georgia, 28 adults with bacteriologically confirmed pulmonary pre-XDR or XDR-TB were randomized 1:1 to receive standard-of-care (SoC) alone (n=14) or SoC plus ibuprofen 400 mg daily for 2 months (n=14), with 6 months of follow-up. Primary endpoints were sputum culture conversion and radiological improvement. Secondary endpoints included WHO-defined outcomes, safety, health-related quality of life, and inflammatory markers. By month 2, culture negativity was achieved in 27% of controls and 9% of ibuprofen recipients, with median conversion time of 4 months in both groups. Radiological improvement was observed in 64% vs 54% at month 2, and in 90% of both groups by month 6. Final outcomes were comparable (71% cured), and adverse events did not differ. Ibuprofen was associated with reductions in inflammatory markers, including monocyte-to-lymphocyte ratio and interferon gamma. Adjunctive ibuprofen did not improve primary endpoints but showed immune-modulating activity with a favourable safety profile, supporting further investigation in larger studies.</p>
2026-05-28 | MTBLS13376 | MetaboLights
Project description:Given the dearth of new antibiotics, host-directed therapies (HDTs) are especially desirable. Since IFN-gamma (IFNγ) plays a central role in host resistance to intracellular bacteria, including Mycobacterium tuberculosis, we searched for small molecules to augment the IFNγ response in macrophages. Using a novel screen we identified a compound belonging to the rocaglate family(CMLD009433) that synergize with a sub-threshold concentration of IFNγ to enhance macrophage activation. We used microarrays to detail the global programme of gene expression mediated by the rocaglate CMLD009433(C9433) and identified upregulation of several important regulatory genes important for host defense.
2016-11-01 | GSE72435 | GEO
Project description:Metformin, the most widely administered diabetes drug, has been proposed as a candidate for host directed therapy for tuberculosis although very little is known about its effects on human host responses to Mycobacterium tuberculosis. When added in vitro to PBMCs isolated from healthy non-diabetic volunteers, metformin increased glycolysis, inhibited the mTOR targets, strongly reduced M. tuberculosis induced production of TNF-alpha (-58%), IFN-gamma (-47%) and IL-beta (-20%), while increasing phagocytosis. In healthy subjects, in vivo metformin intake induced significant transcriptional changes in whole blood and isolated PBMCs, with substantial down-regulation of genes related to inflammation and the type 1 interferon response. Metformin intake also increased monocyte phagocytosis (by 1.5 to 2 fold) and ROS production (+20%). These results show that metformin in humans has a range of potentially beneficial effects on cellular metabolism, immune function and gene-transcriptional level, that affect innate host responses to M. tuberculosis. This underlines the importance of cellular metabolism for host immunity and supports a role for metformin as host-directed therapy for tuberculosis.
2019-06-16 | GSE102677 | GEO
Project description:Metformin, the most widely administered diabetes drug, has been proposed as a candidate for host directed therapy for tuberculosis although very little is known about its effects on human host responses to Mycobacterium tuberculosis. When added in vitro to PBMCs isolated from healthy non-diabetic volunteers, metformin increased glycolysis, inhibited the mTOR targets, strongly reduced M. tuberculosis induced production of TNF-α (-58%), IFN-gamma (-47%) and IL-1β (-20%), while increasing phagocytosis. In healthy subjects, in vivo metformin intake induced significant transcriptional changes in whole blood and isolated PBMCs, with substantial down-regulation of genes related to inflammation and the type 1 interferon response. Metformin intake also increased monocyte phagocytosis (by 1.5 to 2 fold) and ROS production (+20%). These results show that metformin in humans has a range of potentially beneficial effects on cellular metabolism, immune function and gene-transcriptional level, that affect innate host responses to M. tuberculosis. This underlines the importance of cellular metabolism for host immunity and supports a role for metformin as host-directed therapy for tuberculosis.
2019-06-16 | GSE102633 | GEO
Project description:Background: Anti-tuberculosis drugs, mainly developed more than 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multi-resistant strains of Mycobacterium tuberculosis are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy (HDT) has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, we evaluated the impact of two host-directed compounds, namely MC3465 and MC3209, on the response of human monocytes-derived macrophages infected with Mycobacterium tuberculosis (MTB). Results: The expression of 181 genes was differentially regulated following MC3465 treatment (p-value < 0.05, log FC ≥ 0.5 and ≤ -0.5) after 4 h, with 53 being upregulated and 128 being downregulated. The expression of more genes was affected after 24h of treatment. 224 genes were upregulated and 652 genes downregulated. (p value < 0.05, log FC ≥ 0.5 and ≤ -0.5). We classified those differentially expressed genes by performing gene-set enrichment analysis using ClueGO cluster analysis. The gene set downregulated by MC3465 at 4 h was significantly enriched for genes associated with chemotaxis and cellular zinc ion homeostasis and cell chemotaxis. At 24 h, most of the downregulated genes belongs to the innate immune response and the cytokine response, with many genes belonging to the type I IFN pathway. Conclusions: Our results indicate that MC3465 alters zinc homeostasis in human macrophages.
2024-03-04 | GSE222412 | GEO
Project description:Maintenance of mitochondrial homeostasis is required to balance the host-pathogen interface during Mycobacterium tuberculosis (Mtb) infection of macrophages. Here, we implicate the non-canonical TRIM family member TRIM14 in regulating mitochondrial health during Mtb infection. Specifically, we show that TRIM14 constrains apoptosis by maintaining a mitochondrial pool of STAT3. TRIM14-dependent mito-STAT3 limits mitochondrial permeability transition pore opening, thereby preserving mitochondrial integrity and raising the threshold for apoptotic commitment. In the absence of TRIM14, increased STAT3 Ser754 phosphorylation reduces mitochondrial STAT3 localization, promoting mPTP opening and apoptosis. In vivo, Trim14 deficiency enhances apoptosis during Mtb infection and is associated with increased CD8+ T cell activation, consistent with apoptotic cell-driven antimycobacterial immunity. Together, these findings define a TRIM14–mito-STAT3 axis that suppresses protective apoptosis during Mtb infection and pinpoint mito-STAT3 as a potential target for host-directed tuberculosis therapies.
2026-06-22 | GSE336086 | GEO
Project description:Inflammation is critical for controlling infections but can cause disease when unchecked. For tuberculosis, the leading cause of death by infection, neutrophil-dominated inflammation is associated with disease progression, emphasizing the need to understand how neutrophil functions are regulated during Mycobacterium tuberculosis infection. Atg5 was the first gene shown to specifically function within neutrophils to promote control of M. tuberculosis. ATG5 is best studied for its role in autophagy, however, the protective activity of ATG5 in neutrophils was unexpectedly independent of other autophagy proteins and remained elusive. We report that ATG5 is required in neutrophils to suppress type I interferon-induced neutrophil extracellular trap (NET) release and swarming during M. tuberculosis infection. Elevated NET release contributes to the early susceptibility of Atg5fl/fl-LysM-Cre mice during infection. These findings identify ATG5 as a master regulator of how type I interferon influences neutrophil responses during infection, revealing a new potential target for host-directed therapies.
2025-03-07 | GSE280193 | GEO