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BACH1 is a central regulator of glutathione and iron metabolism, necrotic cell death and host resistance in Mycobacterium tuberculosis infection

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE236053 | GEO | 2023/06/30

REPOSITORIES: GEO

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Project description:Analysis of Mtb infected murine macrophages derived from C57Bl/6 WT, TPL2KO, IFNARKO & TPL2IFNAR DKO mice [Set 1] Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL?12, IL?1 and TNF??, as well as IFN?? and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL?10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease. Macrophages were derived from C57Bl/6 bone marrow, plated and infected with Mtb H37Rv (or not) in duplicate wells. Samples were then harvested for RNA at time 0 (uninfected only), 15m, 30m, 1hr, 3hr, 6hr and 24hr.

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BACH1 is a central regulator of glutathione and iron metabolism, necrotic cell death and host resistance in Mycobacterium tuberculosis infection

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