c-Myc inhibits macrophage antimycobacterial response in Mycobacterium tuberculosis infection
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Mycobacterium tuberculosis (MTB) is a major global cause of mortality worldwide, responsible for over a million deaths annually. 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 investigation into this phenotype revealed a strong association between c-Myc signaling and macrophage function in MTB control, as identified using unbiased in vitro systems approaches. Given the challenge of perturbing c-Myc in primary cells, we developed a lentiviral system for c-Myc inhibition and overexpression. Using a tetracycline-inducible Omomyc system - a small peptide inhibitor of c-Myc - we show that c-Myc inhibition promotes a pro-inflammatory macrophage phenotype with enhanced anti-mycobacterial activity. Mechanistically, c-Myc inhibition induces metabolic reprogramming via increased mTORC1 activity, leading to upregulated inducible nitric oxide synthase and improved bacterial clearance. In vivo analyses, including murine models and human clinical histopathology, reveal a strong correlation between c-Myc expression and MTB persistence, as well as active tuberculosis (TB), suggesting a role for c-Myc in immune evasion. These findings reveal c-Myc as a potential mediator of immune privilege in MTB infection and highlight its role as a promising target for novel TB therapies aimed at enhancing macrophage function.
Author Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a major global health threat. While most people exposed to MTB successfully fight off the infection, some individuals develop active disease. Understanding how the bacteria evade immune defenses is key to developing better treatments. In this study, we identify a new role for c-Myc, a protein well-known in cancer research, in suppressing the ability of immune cells called macrophages to fight MTB. Macrophages are responsible for engulfing and killing bacteria, but we found that c-Myc interferes with this process, allowing MTB to survive. Using a small peptide inhibitor called Omomyc, we were able to block c-Myc activity, which restored macrophages’ ability to kill MTB. This effect is linked to changes in cellular metabolism, leading to the increased production of molecules essential for bacterial destruction. We also discovered that high c-Myc levels are associated with persistent MTB infection in both mouse models and human tissues. This suggests that c-Myc helps the bacteria evade immune attack, contributing to long-term infection. Our findings reveal a previously unknown mechanism exploited by MTB to survive in the body and suggest that targeting c-Myc could be a promising approach to enhancing immune defenses against TB. By bridging insights from cancer biology and infectious disease research, our work provides a new perspective on tackling TB and highlights c-Myc as a potential therapeutic target for boosting immunity against this deadly infection.
