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Granuloma Dual RNA-Seq Reveals Composite Transcriptional Programs Driven by Neutrophils and Necrosis within Tuberculous Granulomas

ABSTRACT: Granuloma Dual RNA-Seq Reveals Composite Transcriptional Programs Driven by Neutrophils and Necrosis within Tuberculous Granulomas

PROVIDER: PRJNA1224258 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32360500_1.fastq.gz	Fastqsanger.gz
	SRR32360500_2.fastq.gz	Fastqsanger.gz
	SRR32360501_1.fastq.gz	Fastqsanger.gz
	SRR32360501_2.fastq.gz	Fastqsanger.gz
	SRR32360502_1.fastq.gz	Fastqsanger.gz

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Granuloma Dual RNA-Seq Reveals Composite Transcriptional Programs Driven by Neutrophils and Necrosis within Tuberculous Granulomas

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Paired single-cell and spatial transcriptional profiling reveals a central osteopontin macrophage response mediating tuberculous granuloma formation in humans and zebrafish [Spatial Transcriptomics]

Project description:Mycobacterial granulomas are categorical manifestations of tuberculosis pathogenesis. They result from an ensemble of immune responses to Mycobacterium tuberculosis infection, but the identities, arrangement, cellular interactions and regulation of the cells that comprise them has thus far been incompletely understood. We conducted spatial and single-cell RNA sequencing of clinical granuloma biopsy specimens from tuberculosis patients. We found that granulomas consist of concentric transcriptional laminae surrounding areas of central necrosis. Gene expression programs associated with regional architecture were conserved among samples. We identified distinct populations of granuloma-associated stromal cells, fibroblasts, lymphocytes, mast cells, dendritic cells, neutrophils and macrophages. Populations further differentiate into multiple granuloma-specific states that correlate with location. We used inferential analysis to predict dominant granuloma cell-cell interactions, the activity of major signaling pathways, and differential transcription factor activities. Using spatial deconvolution, we mapped a conserved pattern of cellular organization dominated by macrophages rich in osteopontin/SPP1 expression. Trajectory analysis of macrophage subtypes mapped their differentiation and supported the importance of SPP1 to granuloma macrophage polarization. Cumulatively, we have identified a dominant macrophage granuloma population as well as its central regulatory gene in human samples and confirmed its importance to granuloma biology in vivo.

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Gene expression profiles of caseous human pulmonary TB granulomas derived from TB patients

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Single-cell and spatial architecture of human tissue granulomas reveals an aberrant immune-regulatory program underlying sarcoidosis [spatial transcriptomics data]

Project description:Purpose: Granulomas are lumps of immune cells that can form in various organs, causing chronic inflammation and tissue destruction. While most granulomas appear histologically heterogeneous and unstructured, they have a certain resemblance of lymphoid organ formation. We thus pursued the hypothesis that granuloma formation is a highly orchestrated process that mixes and repurposes various regulatory mechanisms of normal development Methods: We performed single-cell sequencing and spatial transcriptomics on granulomas from patients diagnosed with cutaneous sarcoidosis, and we bioinformatically reconstructed their gene-regulatory networks and cell-cell interactions Results: We observed regulatory processes underlying granuloma formation that were highly conserved across individuals and followed characteristic spatial patterns. We identified metabolically reprogrammed macrophages, various T cells subsets and structural cells including fibroblasts and endothelial cells as key players in granulomas. Specifically, exhausted interferon-gamma-producing Th17.1 cells with cytotoxic potential and inflammatory fibroblasts were identified as drivers of granuloma formation by attracting various immune cell types. Summary: we found that granuloma formation in sarcoidosis is a molecular and cellular process that adopts specific aspects of normal lymphoid organ development in aberrant combinations. Our study frames human granuloma formation as a developmental pathology and raises the future perspective of therapeutic targeting of granuloma-specific regulatory programs.

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