BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility
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Published:2023-12-08
Issue:1
Volume:9
Page:120-135
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ISSN:2058-5276
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Container-title:Nature Microbiology
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language:en
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Short-container-title:Nat Microbiol
Author:
Amaral Eduardo P.ORCID, Namasivayam SivaranjaniORCID, Queiroz Artur T. L.ORCID, Fukutani Eduardo, Hilligan Kerry L.ORCID, Aberman Kate, Fisher LoganORCID, Bomfim Caio Cesar B.ORCID, Kauffman KeithORCID, Buchanan Jay, Santuo Leslie, Gazzinelli-Guimaraes Pedro HenriqueORCID, Costa Diego L.ORCID, Teixeira Mariane Araujo, Barreto-Duarte Beatriz, Rocha Clarissa GurgelORCID, Santana Monique Freire, Cordeiro-Santos MarceloORCID, Barber Daniel L.ORCID, Wilkinson Robert J.ORCID, Kramnik IgorORCID, Igarashi KazuhikoORCID, Scriba ThomasORCID, Mayer-Barber Katrin D.ORCID, Andrade Bruno B.ORCID, Sher AlanORCID
Abstract
AbstractOxidative 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.
Funder
Wellcome Trust Ministry of Science, Technology and Innovation | Conselho Nacional de Desenvolvimento Científico e Tecnológico Foundation for the National Institutes of Health
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Microbiology (medical),Genetics,Applied Microbiology and Biotechnology,Immunology,Microbiology
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