BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility.
Nat Microbiol
; 9(1): 120-135, 2024 Jan.
Article
en En
| MEDLINE
| ID: mdl-38066332
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.
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1
Base de datos:
MEDLINE
Asunto principal:
Tuberculosis
/
Tuberculosis Pulmonar
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Mycobacterium tuberculosis
Idioma:
En
Revista:
Nat Microbiol
Año:
2024
Tipo del documento:
Article