BACH1 is a central regulator of glutathione metabolism, cellular necrosis and host resistance in Mycobacterium tuberculosis infection
Background. An exacerbated oxidative stress response can regulate cellular necrosis by triggering lipid peroxidation in an iron-dependent manner and this form of necrotic death has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. Here we examined the role of Bach1, a transcription factor that represses a major set of antioxidant genes, in regulating host resistance to Mtb. We found that BACH1 expression is associated with and predicts active pulmonary tuberculosis in humans. In response to Mtb infection in vitro and in vivo, ablation of Bach1 increased the levels of glutathione as well as enhanced the expression of Gpx4, an enzyme that regulates lipid peroxidation. Consistent with these observations, Bach1-/- macrophages exhibited increased resistance to Mtb-induced cell death and infected Bach1-deficient mice displayed a striking reduction in bacterial loads as well as pulmonary necrosis and lipid peroxidation accompanied by enhanced survival. In addition, single-cell RNAseq analysis of the lungs of Mtb-infected Bach1-/- mice revealed an enrichment of genes associated with suppression of ferroptosis. Finally, deletion of Bach1 in B6.Sst1S mice, an inbred strain that exhibits the necrotic lung pathology similar to that seen in human TB, enhanced host resistance to Mtb while significantly reducing tissue necrosis. These findings identify Bach1 and its regulation of the oxidative stress response as an important modulator of cellular and tissue necrosis as well as host resistance in Mtb infection. Overall design: Gene expression analysis on Mtb-infected and uninfected B6.Sst1s and  B6.Sst1sBach1-/- mice