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Paired single-cell and spatial transcriptional profiling reveals a central osteopontin macrophage response mediating tuberculous granuloma formation

ABSTRACT: Paired single-cell and spatial transcriptional profiling reveals a central osteopontin macrophage response mediating tuberculous granuloma formation

PROVIDER: PRJNA1257824 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR33397789.fastq.gz	Fastqsanger.gz
	SRR33397790.fastq.gz	Fastqsanger.gz
	SRR33397791.fastq.gz	Fastqsanger.gz
	SRR33397793.fastq.gz	Fastqsanger.gz

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

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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 [scRNA-Seq]

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Lymphoid function of the tuberculous granuloma

Project description:Induced lymphoid structures associated with pulmonary granulomas have been observed during TB in both humans and mice and could orchestrate host defense. In order to determine whether granulomas perform lymphoid functions, mice lacking secondary lymphoid organs (SLOs) were infected with Mycobacterium tuberculosis (MTB). As in wild type mice (WT), granulomas developed, MTB was controlled, and antigen-specific T cell responses including T central memory (TCM) cells were generated in the complete absence of SLOs. Moreover, T cell activation correlated with granuloma formation in these mice and TCM cells accumulated in lungs and participated in protection against secondary MTB infection. Lung granulomas may therefore represent tertiary lymphoid organs (TLOs) capable of priming robust T cell responses and mediating host defense during chronic MTB at the site of infection.

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A Non-Canonical Type 2 Immune Response Coordinates Tuberculous Granuloma Formation and Epithelialization

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

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