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: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: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:Infectious diseases, such as Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), remain a global health threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a complementing strategy for infection treatment through targeting host immune mechanisms. However, the limited understanding of the host factors and their regulatory mechanisms involved in host immune defense against infections has impeded HDT development. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) elicits host protective immunity against Mtb. Mechanistically, TRIM27 enters host cell nucleus upon Mtb infection to function as a transcription activator of transcription factor EB (TFEB). TRIM27 binds to TFEB promoter and the TFEB transcription factor cAMP responsive element binding protein 1 (CREB1), thus enhancing CREB1-TFEB promoter binding affinity and promoting CREB1 transcription activity towards TFEB, eventually leading to autophagy activation and pathogen clearance. Thus, TRIM27 contributes to host anti-Mtb immunity and targeting TRIM27/CREB1/TFEB axis serves as a promising HDT-based TB treatment.
2024-07-03 | GSE237039 | GEO
Project description:Host directed activity of Pyrazinamide in Mycobacterium tuberculosis infection
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Project description:Repurposing Tamoxifen as Potential Host-Directed Therapeutic For Tuberculosis
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Project description:This study revealed pathogenic role of pre-BCR-independent SYK activation in high-risk B-ALL. Intensified and central nervous system (CNS)-directed chemotherapy has significantly improved outcomes for pediatric B-acute lymphoblastic leukemia (B-ALL), but confers significant late-effect morbidities. Moreover, many patients suffer relapses, underscoring the need to develop novel, molecularly targeted B-ALL therapies. Using a mouse model, we showed that leukemic B-cells require pre-B-cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) signaling in vivo. In diagnostic samples from human B-ALL patients, SYK and downstream targets were phosphorylated regardless of pre-BCR expression or genetic subtype. Two small molecule SYK inhibitors, fostamatinib and BAY61-3606, attenuated growth of 69 B-ALL samples, including high-risk (HR) subtypes. Orally administered fostamatinib significantly reduced high disease burden after xenotransplantation of HR B-ALL samples into immune-deficient mice, and decreased leukemia dissemination into spleen, liver, kidneys and the CNS of recipients. Thus, SYK activation sustains growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL. B-cell leukemia samples (3) from a mutant mouse model were compared to sorted or cultured preB or proB cells from normal mice using Affymetrix GeneChip arrays.
2014-03-29 | E-GEOD-56345 | biostudies-arrayexpress