BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility

BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility. Amaral, E. P., Namasivayam, S., Queiroz, A. T., Fukutani, E., Hilligan, K. L., Aberman, K., Fisher, L., Bomfim, C. C. B., Kauffman, K., Buchanan, J., Santuo, L., Gazzinelli-Guimaraes, P. H., Costa, D. L., Teixeira, M. A., Barreto-Duarte, B., Rocha, C. G., Santana, M. F., Cordeiro-Santos, M., Barber, D. L., Wilkinson, R. J., Kramnik, I., Igarashi, K., Scriba, T., Mayer-Barber, K. D., Andrade, B. B., & Sher, A. Nature Microbiology 2023, 13:10.1038/s41564–023–01523–7, Nature Publishing Group, dec, 2023.

Paper doi abstract bibtex

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

@article{Amaral2023,
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. The host transcription factor, Bach1, promotes Mycobacterium tuberculosis pathogenesis by inhibiting protective glutathione metabolism and antioxidant responses that prevent ferroptosis.},
author = {Amaral, Eduardo P. and Namasivayam, Sivaranjani and Queiroz, Artur T.L. and Fukutani, Eduardo and Hilligan, Kerry L. and Aberman, Kate and Fisher, Logan and Bomfim, Caio Cesar B. and Kauffman, Keith and Buchanan, Jay and Santuo, Leslie and Gazzinelli-Guimaraes, Pedro Henrique and Costa, Diego L. and Teixeira, Mariane Araujo and Barreto-Duarte, Beatriz and Rocha, Clarissa Gurgel and Santana, Monique Freire and Cordeiro-Santos, Marcelo and Barber, Daniel L. and Wilkinson, Robert J. and Kramnik, Igor and Igarashi, Kazuhiko and Scriba, Thomas and Mayer-Barber, Katrin D. and Andrade, Bruno B. and Sher, Alan},
doi = {10.1038/s41564-023-01523-7},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Amaral et al. - 2023 - BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility.pdf:pdf},
issn = {2058-5276},
journal = {Nature Microbiology 2023},
keywords = {Cell death,Cell death and immune response,OA,Tuberculosis,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
pages = {10.1038/s41564--023--01523--7},
publisher = {Nature Publishing Group},
title = {{BACH1 promotes tissue necrosis and \textit{Mycobacterium tuberculosis} susceptibility}},
url = {https://www.nature.com/articles/s41564-023-01523-7},
volume = {13},
year = {2023}
}

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