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Host eicosanoid signals define a granuloma-associated fibroblast population coordinating mycobacterial containment II

ABSTRACT: We used single-cell RNA sequencing to interrogate granulomas from Mycobacterium marinum infected zebrafish (Danio rerio) of a genetic mutant and matched WT siblings. Granulomas are comprised of several cell types and we sought to understand the consequences of genetic disruption of the gene apolipoprotein db (apodb) on granuloma cells types and cell-specific transcription.

ORGANISM(S): Danio rerio

PROVIDER: GSE324157 | GEO | 2026/07/31

REPOSITORIES: GEO

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Host eicosanoid signals define a granuloma-associated fibroblast population coordinating mycobacterial containment

Project description:We used single-cell RNA sequencing to interrogate granulomas from Mycobacterium marinum infected zebrafish (Danio rerio) of a genetic mutant. This sample was compared to a previously published granuloma scRNAseq dataset from wildtype zebrafish. Granulomas are comprised of several cell types and we sought to understand the consequences of genetic disruption of the gene leukotriene A4 hydrolase (lta4h) on granuloma cells types and cell-specific transcription. This is the first comparison of mycobacterial granuloma scRNAseq from a genetic mutant to wildtype.

2026-07-31 | GSE299987 | GEO

Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection

Project description:Mycobacterium tuberculosis infection in humans triggers formation of granulomas, tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. We find that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. Using the zebrafish-Mycobacterium marinum model, we identify fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function results in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. In humans, we find that granuloma macrophages are similarly transformed. Long considered largely through the prism of immune signaling pathways, granuloma macrophages are reprogrammed by epithelial modules that alter the trajectory of mycobacterial infection.

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Wildtype granuloma cells from M. marinum-infected zebrafish

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

Project description:Using the zebrafish-M. marinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-seq analysis of zebrafish granulomas as well as analysis of M. tuberculosis-infected macaques reveal that, even in the presence of robust type 1 immune responses, countervailing type 2 signals associate with macrophage epithelialization. We find that type 2 immune signaling, mediated via stat6, is absolutely required for epithelialization and granuloma formation.

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

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. Using the Mycobacterium marinum-zebrafish model we found that mycobacterial infection induces spp1 expression in macrophages and that spp1 ablation results in granuloma formation defects and reduced survival in adult animals. To determine the impact of mycobacterial infection on the transcriptional response of nascent granuloma macrophages we conducted bulk RNA-seq on flow-sorted infected and uninfected macrophages isolated from infected larvae or uninfected controls.

2025-06-13 | GSE296119 | GEO

Proteomic analysis of Mycobacterial Biofilm Matrix and Development of Biofilm-binding Synthetic Nanobodies

Project description:Tissue-penetrating nanobodies as drug-delivery vehicles have shown efficacy in treating hard-to-reach and -treat diseases. The present study reports nanobodies with application potential in the treatment of tuberculosis (TB), especially the antibiotic tolerant biofilms that form in TB granulomas. Using Mycobacterium marinum (Mmr) as a model pathogen, we identified the most abundant matrix proteins in cultured biofilms and granuloma biofilms from infected zebrafish, and used them as targets to produce synthetic nanobodies (sybodies). Surface-exposed proteins on Mmr biofilms were identified using a combination of in vitro cell surface biotinylation proteomics andex vivo proteomics on granulomas extracted from Mmr-infected adult zebrafish. We identified a total of 3080 and 41 mycobacterial biofilm matrix-associated proteins by in vitro and ex vivo proteomics, respectively. The molecular chaperones GroEL1 and GroEL2 were identified in both datasets, and fulfilled the criteria of ideal nanobody targets. We created sybodies against GroEL1 and GroEL2, and showed that they bind the intact in vitro and ex vivo Mmr-biofilms. Taken together, the present study reports a proof-of-concept showing that biotinylation proteomics of biofilms complemented with ex vivo proteomics of granuloma biofilms is a valuable strategy to uncover optimal nanobody targets within the biofilm matrix. Nanobody-based strategies have great potential to provide new and much-needed solutions for more effective treatment of tuberculosis, as well asother chronic biofilm infections with increased antibiotic tolerance and high risk for emerging antibiotic resistance

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Bulk RNA-seq of laser-microdissected granuloma and adjacent non-granuloma regions from FFPE lung tissues of pulmonary sarcoidosis

Project description:Sarcoidosis is a systemic granulomatous disease with heterogeneous organ involvement and clinical outcomes. To characterize transcriptional features associated with pulmonary sarcoid granulomas, we performed bulk RNA sequencing of laser-microdissected granuloma regions and adjacent non-granuloma regions from formalin-fixed paraffin-embedded (FFPE) lung tissue specimens obtained from patients with pulmonary sarcoidosis. The dataset includes paired regional samples derived from clinically obtained lung specimens. These data provide a resource for investigating localized gene expression differences associated with granuloma formation in pulmonary sarcoidosis.

2026-04-23 | GSE328831 | GEO

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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Aberrant lipid metabolism in macrophages is associated with granuloma formation in sarcoidosis

Project description:Rationale: Chronic sarcoidosis is a complex granulomatous disease with limited treatment options that can progress over time. Understanding the molecular pathways contributing to disease would aid in new therapeutic development. Objectives: To understand if macrophages from non-resolving chronic sarcoidosis patients are predisposed to macrophage aggregation and granuloma formation, and if modulation of the underlying molecular pathways influence sarcoidosis granuloma formation. Methods: Macrophages were cultivated in vitro from isolated peripheral blood CD14+ monocytes and evaluated for spontaneous aggregation. Transcriptomics analyses, phenotypic and drug inhibitory experiments were performed on these monocyte-derived macrophages. Human skin biopsies from sarcoidosis patients and a myeloid Tsc2-specific sarcoidosis mouse model were analyzed for validatory experiments. Measurements and Main Results: Monocyte-derived macrophages from chronic sarcoidosis patients spontaneously formed extensive granulomas in vitro compared to healthy controls. Transcriptomic analyses separated healthy and sarcoidosis macrophages and identified an enrichment in lipid metabolic processes. In vitro patient granulomas, sarcoidosis mouse model granulomas, and those directly analyzed from lesional patient skin expressed an aberrant lipid metabolism profile and contained increased neutral lipids. Conversely, a combination of statins and cholesterol-reducing agents reduced granuloma formation both in vitro and in vivo in a sarcoidosis mouse model. Conclusions: Together, our findings show that altered lipid metabolism in sarcoidosis macrophages is associated with its predisposition to granuloma formation and suggest cholesterol-reducing therapies as a treatment option in patients.

2024-12-31 | GSE251802 | GEO

Ex vivo proteomics of Mycobacterium marinum

Project description:Proteins expressed and exported out of the mycobacterial biofilm cells into granulomatous environment during infection were identified by LC-MS/MS. To this end, adult 5- to 10-month-old female AB wild-type zebrafish (Danio rerio) were infected with 4-day old M. marinum ATCC927 (carrying the pTEC27 plasmid expressing the tdTomato fluorescent protein) cells. After 8 weeks post infection, ten zebrafish were euthanized, and red fluorescent mycobacterial granulomas were carefully dissected from the zebrafish ovaries. Ten granulomas were collected per tube, frozen on dry ice and stored at -80 °C until preparation for proteomics. Altogether, ten replicate samples, each with ten mycobacterial granulomas, were subjected to protein extraction and LC-MS/MS identification.

2023-03-06 | PXD039416 | Pride

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