Lipid Peroxidation and Type I Interferon Coupling Fuels Pathogenic Macrophage Activation Causing Tuberculosis...

Area of Science:

• Immunology
• Microbiology
• Genetics

Background:

• Tuberculosis (TB) affects a quarter of the global population, yet only a fraction develop active disease.
• Understanding the host factors driving TB pathogenesis is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the mechanisms underlying necrotic lung granuloma formation in a novel sst1-susceptible mouse model of TB.
• To identify host-directed therapeutic targets for pulmonary TB.

Main Methods:

• Development of a genetically defined sst1-susceptible mouse model.
• Analysis of macrophage activation pathways, iron metabolism, and ferroptosis in response to Mycobacterium tuberculosis (Mtb) and TNF stimulation.
• Correlation of Myc pathway upregulation with TB patient outcomes.

Main Results:

• The sst1-susceptible mouse model recapitulated necrotic lung granulomas, a hallmark of human TB.
• Aberrant macrophage activation, driven by conflicting Myc and antioxidant pathways, impaired iron sequestration and ferroptosis inhibition.
• Sustained Type I Interferon (IFN-I) hyperactivity and iron-mediated lipid peroxidation compromised macrophage resistance to Mtb.
• Upregulation of the Myc pathway in TB patients correlated with poor treatment outcomes.

Conclusions:

• Dysregulated Myc pathways in activated macrophages contribute to aberrant macrophage activation and TB pathogenesis.
• Impaired iron homeostasis and ferroptosis are critical in driving Mtb-induced lung necrosis.
• Targeting Myc dysregulation in macrophages presents a promising host-directed therapeutic strategy for TB.