Turning off c-Myc helps immune cells fight tuberculosis

Tuberculosis remains a major global killer, with Mycobacterium tuberculosis (MTB) causing over a million deaths each year, yet most people exposed to the bacterium do not develop disease. Researchers led by Cédric Dollé asked why the innate immune system succeeds so often, and how it sometimes fails. Building on earlier work that identified interferon-gamma (IFN-γ) as a central regulator of early defense against MTB, the team focused on how the timing of IFN-γ exposure affects macrophages, the frontline immune cells that swallow and try to destroy the bacteria. To explore this, the researchers used unbiased in vitro systems approaches to profile macrophage behavior, and coupled those laboratory studies with in vivo analyses that included murine models and examination of human clinical histopathology. Because manipulating certain regulatory genes in primary cells can be difficult, the group also developed a lentiviral system to control gene expression directly in macrophages. This combination of cell-based experiments, genetic tools and tissue studies allowed the team to link basic immune signaling events to patterns observed in animal models and human disease samples.

The study produced several clear findings about timing, signaling and mechanism. The researchers show that IFN-γ exposure before infection enhances macrophage antibacterial activity, while IFN-γ given after infection does not produce the same benefit. An unexpected connection emerged between macrophage function and the proto-oncogene c-Myc from the unbiased in vitro analyses. To test causality the team used a lentiviral system for c-Myc inhibition and overexpression, and a tetracycline-inducible Omomyc system - a small peptide inhibitor of c-Myc - to dial c-Myc activity up or down. Inhibiting c-Myc shifted macrophages toward a pro-inflammatory phenotype and improved their antimycobacterial activity. Mechanistic work showed that c-Myc inhibition induces metabolic reprogramming through increased mTORC1 activity, which in turn leads to upregulated inducible nitric oxide synthase and better bacterial control. Finally, the in vivo analyses in murine models and human histopathology revealed a strong correlation between high c-Myc expression, MTB persistence and active tuberculosis.

Taken together, these results position c-Myc as a potential mediator of immune privilege in MTB infection and a promising target for new treatments that aim to boost macrophage function. The work suggests that the immune system’s success against MTB depends not only on whether key signals like IFN-γ are present, but also on when they arrive; pre-exposure can prime macrophages for better killing. By showing that c-Myc inhibition rewires macrophage metabolism via mTORC1 and increases inducible nitric oxide synthase, the study links molecular pathways to measurable changes in bacterial control and to patterns seen in animal models and human tissue. These insights open a path toward therapies that would modulate host pathways—such as c-Myc—instead of, or alongside, directly targeting the bacterium, with the goal of reducing persistence and improving outcomes in TB.