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Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets II

ABSTRACT: Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets II

PROVIDER: PRJNA730552 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14570200_1.fastq.gz	Fastqsanger.gz
	SRR14570200_2.fastq.gz	Fastqsanger.gz
	SRR14570201_1.fastq.gz	Fastqsanger.gz
	SRR14570201_2.fastq.gz	Fastqsanger.gz
	SRR14570202_1.fastq.gz	Fastqsanger.gz

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Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets

Project description:Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets

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Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets II

Project description:Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets II

| PRJNA730552 | ENA

Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets

Project description:We hypothesised that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a non-infectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared three primary human cell culture models at the whole transcriptome level, and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified twelve intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

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Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets II

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Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets.

Project description:Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

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Project description:Rationale: Despite the availability of multi-“omics” strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. Objective: To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis).

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