作者
Eduardo Pinheiro Amaral,Sivaranjani Namasivayam,Artur T. L. Queiroz,Eduardo R. Fukutani,Kerry L. Hilligan,Kate Aberman,Logan Fisher,Caio César Barbosa Bomfim,Keith D. Kauffman,J. Arthur Buchanan,Leslie Santuo,Pedro Henrique Gazzinelli-Guimarães,Diego L. Costa,Maria Glória Teixeira,Beatriz Barreto-Duarte,Clarissa Araújo Gurgel Rocha,Monique Freire Santana,Marcelo Cordeiro-Santos,Daniel L. Barber,Robert J. Wilkinson,Igor Kramnik,Kazuhiko Igarashi,Thomas J. Scriba,Katrin D. Mayer‐Barber,Bruno B. Andrade,Alan Sher
摘要
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.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.