BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility
File(s)
Author(s)
Type
Journal Article
Abstract
Oxidative stress triggers ferroptosis, a form of cellular necrosis characterized by iron-dependent lipid peroxidation, and has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. We investigated whether Bach1, a transcription factor that represses multiple antioxidant genes, regulates host resistance to Mtb. We found that BACH1 expression is associated clinically with active pulmonary tuberculosis. Bach1 deletion in Mtb-infected mice increased glutathione levels and Gpx4 expression that inhibit lipid peroxidation. Bach1-/- macrophages exhibited increased resistance to Mtb-induced cell death, while Mtb-infected Bach1-deficient mice displayed reduced bacterial loads, pulmonary necrosis and lipid peroxidation concurrent with increased survival. Single-cell RNA-seq analysis of lungs from Mtb-infected Bach1-/- mice revealed an enrichment of genes associated with ferroptosis suppression. Bach1 depletion in Mtb-infected B6.Sst1S mice that display human-like necrotic lung pathology also markedly reduced necrosis and increased host resistance. These findings identify Bach1 as a key regulator of cellular and tissue necrosis and host resistance in Mtb infection.
Date Issued
2024-01
Date Acceptance
2023-10-11
Citation
Nature Microbiology, 2024, 9 (1), pp.120-135
ISSN
2058-5276
Publisher
Nature Research
Start Page
120
End Page
135
Journal / Book Title
Nature Microbiology
Volume
9
Issue
1
Copyright Statement
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. This is a U.S. Government work and not under copyright protection in
the US; foreign copyright protection may apply 2023
the US; foreign copyright protection may apply 2023
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/38066332
Subjects
Animals
Basic-Leucine Zipper Transcription Factors
Macrophages
Mice
Mycobacterium tuberculosis
Necrosis
Tuberculosis
Tuberculosis, Pulmonary
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2023-12-08