A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization

A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1016/j.cell.2021.02.046
Journal or Publication Title: Cell
Volume: 184
Number: 7
Page Range: 1757-1774.e14
Date: 2021
Divisions: Immune-Vascular Interactions
Depositing User: General Admin
Identification Number: 10.1016/j.cell.2021.02.046
ISSN: 00928674
Date Deposited: 10 Jun 2021 05:52
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.

Keywords: IL4R; Mycobacterium; STAT6; epithelialization; granuloma; macrophage; tuberculosis; zebrafish.

Copyright © 2021 Elsevier Inc. All rights reserved.

Creators:
Creators
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Cronan, Mark R.
UNSPECIFIED
Hughes, Erika J.
UNSPECIFIED
Brewer, W. Jared
UNSPECIFIED
Viswanathan, Gopinath
UNSPECIFIED
Hunt, Emily G.
UNSPECIFIED
Singh, Bindu
UNSPECIFIED
Mehra, Smriti
UNSPECIFIED
Oehlers, Stefan H.
UNSPECIFIED
Gregory, Simon G.
UNSPECIFIED
Kaushal, Deepak
UNSPECIFIED
Tobin, David M.
UNSPECIFIED
Last Modified: 10 Jun 2021 05:52
URI: https://eprints.centenary.org.au/id/eprint/996

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