PROJECT ID: GSE161712

Data source GEO: GSE161712
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.
Key word mycobacterium-marinum infection; zebrafish larvae reveals; inflammatory response; mediates resistance; adult zebrafish; tgf-beta; mice; gene; populations; tuberculosis; granuloma; macrophage; epithelialization; Mycobacterium; STAT6; IL4R
Publication Cronan MR, Hughes EJ, Brewer WJ, Viswanathan G et al. A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization. Cell 2021 Apr 1;184(7):1757-1774.e14. PMID: 33761328
Abstract The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma macrophages undergo a dramatic transition in which entire epithelial modules are induced and define granuloma architecture. In tuberculosis, relatively little is known about the host signals that trigger this transition. Using the zebrafish-Mycobacterium marinum model, we identify the basis of granuloma macrophage transformation. Single-cell RNA-sequencing analysis of zebrafish granulomas and analysis of Mycobacterium 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. In mixed chimeras, stat6 acts cell autonomously within macrophages, where it is required for epithelioid transformation and incorporation into necrotic granulomas. These findings establish the signaling pathway that produces the hallmark structure of mycobacterial infection.


Dataset Information

Dataset ID Species Tissue / Organ Experiment type Sample Source dataset ID
1. GSE161712 (M. marinum) Danio rerio granulomas disease adult, infected with bacteria of M. marinum GEO: GSM4913139

Clustering Result

Cluster Cell type Gene id (symbol) Marker class Evidence
1 Epithelialized macrophages ENSDARG00000016771 (tfa) marker DOI:10.1016/j.cell.2021.02.046
2 Epithelialized macrophages ENSDARG00000017624 (krt4) marker DOI:10.1016/j.cell.2021.02.046
3 Epithelialized macrophages ENSDARG00000028618 (krt18b) marker DOI:10.1016/j.cell.2021.02.046
5 Proliferating cells ENSDARG00000024488 (top2a) marker DOI:10.1016/j.cell.2021.02.046
7 Proliferating cells ENSDARG00000054155 (pcna) marker DOI:10.1016/j.cell.2021.02.046
8 Neutrophils ENSDARG00000019521 (mpx) marker DOI:10.1016/j.cell.2021.02.046
9 Monocytes ENSDARG00000088641 (grn2) marker DOI:10.1016/j.cell.2021.02.046
9 Monocytes ENSDARG00000089362 (grn1) marker DOI:10.1016/j.cell.2021.02.046
10 Inflammatory macrophages ENSDARG00000031976 (nos2b) marker DOI:10.1016/j.cell.2021.02.046
10 Inflammatory macrophages ENSDARG00000059294 (marco) marker DOI:10.1016/j.cell.2021.02.046
12 Epithelialized macrophages ENSDARG00000002445 (prdm1a) marker DOI:10.1016/j.cell.2021.02.046
13 T cells ENSDARG00000015752 (zap70) marker DOI:10.1016/j.cell.2021.02.046
15 Red blood cells -- (hbba1.1) marker DOI:10.1016/j.cell.2021.02.046
16 Eosinophils ENSDARG00000100051 (spink2.4) marker DOI:10.1016/j.cell.2021.02.046