c-Myc Inhibits Macrophage Antimycobacterial Response in <i>Mycobacterium tuberculosis</i> Infection

BACKGROUND: Mycobacterium tuberculosis (MTB) remains a major cause of global mortality, yet natural immunity prevents disease in more than 90% of exposed individuals. Interferon gamma (IFN-γ) is a critical regulator of innate immunity and enhances macrophage antimicrobial responses. METHODS: Using in vitro systems approaches, we compared the effects of IFN-γ exposure before versus after infection. We manipulated c-Myc in primary macrophages with a tetracycline-inducible lentiviral system. c-Myc expression was also analyzed in tissues from murine tuberculosis models and human granulomas. RESULTS: Preinfection IFN-γ exposure primed macrophages for enhanced bacterial control, whereas postinfection exposure did not. We identified c-Myc signaling as a central determinant of macrophage antimycobacterial function. Inhibition of c-Myc via Omomyc enhanced bacterial control partly through mTORC1-dependent metabolic reprogramming and nitric oxide production. In vivo analyses, including murine models and human clinical histopathology, revealed strong associations between c-Myc expression, MTB persistence, and active tuberculosis. CONCLUSION: c-Myc mediates immune privilege in MTB infection and represents a promising target for host-directed therapies to enhance macrophage function.