c-Myc Inhibits Macrophage Antimycobacterial Response in Mycobacterium tuberculosis Infection

Mycobacterium tuberculosis (MTB) is a major global cause of mortality, responsible for over a million deaths each year. Despite this burden, natural immunity prevents disease in more than 90% of exposed individuals. Previous studies have identified interferon-gamma (IFN-γ) as a key regulator of innate immune defense against MTB. Here, we investigate the impact of IFN-γ timing on macrophage-mediated control of MTB infection. We demonstrate that IFN-γ exposure before infection enhances macrophage antibacterial activity, whereas post-infection exposure does not. Further analysis of this phenotype revealed a strong association between c-Myc signaling and macrophage function in MTB control, as identified through unbiased in vitro systems approaches. Given the difficulty of perturbing c-Myc in primary cells, we developed a lentiviral system for c-Myc inhibition and overexpression. We profiled both datasets (IFN-γ timing and c-Myc inhibition) to characterize the resulting transcriptional shifts.