c-Myc inhibits macrophage antimycobacterial response in Mycobacterium tuberculosis infection

Abstract

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. In this study, we investigated how IFN-γ timing influences macrophage control of MTB. We found that pre-infection IFN-γ exposure primes macrophages for enhanced bacterial control by activating key antimicrobial pathways, whereas post-infection exposure fails to confer this benefit. Using unbiased in vitro systems approaches, we identified c-Myc signaling as a central determinant of macrophage antimycobacterial function. To manipulate c-Myc in primary cells, we developed a tetracycline-inducible lentiviral system for c-Myc inhibition and overexpression. c-Myc inhibition via Omomyc enhanced macrophage bacterial control 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, implicating c-Myc as a mediator of immune privilege in MTB infection and a promising target for host-directed therapies to enhance macrophage function.

Keywords: IFN-γ; Mycobacterium tuberculosis; Omomyc; c-Myc; granuloma; macrophage activation; metabolic reprogramming; tuberculosis.