BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility

• Published in: Nature microbiology Vol. 9; no. 1; pp. 120 - 135
• Main Authors: Amaral, Eduardo P., Namasivayam, Sivaranjani, Queiroz, Artur T. L., Fukutani, Eduardo, Hilligan, Kerry L., Aberman, Kate, Fisher, Logan, Bomfim, Caio Cesar B., Kauffman, Keith, Buchanan, Jay, Santuo, Leslie, Gazzinelli-Guimaraes, Pedro Henrique, Costa, Diego L., Teixeira, Mariane Araujo, Barreto-Duarte, Beatriz, Rocha, Clarissa Gurgel, Santana, Monique Freire, Cordeiro-Santos, Marcelo, Barber, Daniel L., Wilkinson, Robert J., Kramnik, Igor, Igarashi, Kazuhiko, Scriba, Thomas, Mayer-Barber, Katrin D., Andrade, Bruno B., Sher, Alan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2024; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 14/63; 38/77; 38/91; 631/250/1933; 631/250/255/1856; 631/80/82; 82/51; Animals; Antioxidants; Basic-Leucine Zipper Transcription Factors - genetics; Biomedical and Life Sciences; Cell death; Cell survival; Ferroptosis; Glutathione; Infectious Diseases; Life Sciences; Lipid peroxidation; Lipids; Macrophages; Macrophages - microbiology; Medical Microbiology; Mice; Microbiology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Necrosis; Oxidative stress; Parasitology; Pathogenesis; Transcription factors; Tuberculosis; Tuberculosis - microbiology; Tuberculosis, Pulmonary - genetics; Virology
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-023-01523-7

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.Sst1 S 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. The host transcription factor, Bach1, promotes Mycobacterium tuberculosis pathogenesis by inhibiting protective glutathione metabolism and antioxidant responses that prevent ferroptosis.