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BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility.

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journal contribution
posted on 2024-01-10, 11:42 authored by Eduardo P Amaral, Sivaranjani Namasivayam, Artur TL Queiroz, Eduardo Fukutani, Kerry L Hilligan, Kate Aberman, Logan Fisher, Caio Cesar B Bomfim, Keith Kauffman, Jay Buchanan, Leslie Santuo, Pedro Henrique Gazzinelli-Guimaraes, Diego L Costa, Mariane Araujo Teixeira, Beatriz Barreto-Duarte, Clarissa Gurgel Rocha, Monique Freire Santana, Marcelo Cordeiro-Santos, Daniel L Barber, Robert J Wilkinson, Igor Kramnik, Kazuhiko Igarashi, Thomas Scriba, Katrin D Mayer-Barber, Bruno B Andrade, Alan Sher
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.


Crick (Grant ID: CC2112, Grant title: Wilkinson CC2112)


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