BACH1 is a central regulator of glutathione and iron metabolism, necrotic cell death and host resistance in Mycobacterium tuberculosis infection
Exacerbated oxidative stress response is known to 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) infection and disease. Here we examined the role of Bach1, a transcription factor that represses a major set of antioxidant genes, in regulating host resistance to Mtb. 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 necrosis and infected Bach1-deficient mice displayed a striking reduction in bacterial loads as well as pulmonary necrosis and lipid peroxidation reflected in their enhanced survival. In addition, single-cell RNAseq analysis of the lungs of Mtb-infected Bach1-/- mice revealed an enrichment of a gene signature associated with protection against ferroptotic cell death. Finally, deletion of Bach1 in B6.Sst1S mice, an inbred strain that recapitulates the necrotic lung pathology seen in human TB, enhanced host resistance to Mtb while significantly reducing tissue necrosis. These findings identify Bach1 as an important regulator of cellular and tissue necrosis in Mtb infection and as such a potential target for host-direct therapy of tuberculosis. Overall design: WT and Bach1KO mice were infected with M. tuberculosis via the aerosol route. 23 days post infection lungs were harvested and cells isolated. Sorted live cells were used for scRNAseq processing and analysis