Researchers at the University of Alabama in Birmingham and the Africa Health Research Institute have made a breakthrough in understanding how Mycobacterium tuberculosis, the bacterium that causes tuberculosis, evades the immune response in humans. Previous evidence had pointed to the role of host immunometabolism in this process. Now, a study published in Nature Communications sheds light on how M. tuberculosis disrupts the homeostasis of a high-energy molecule called NADH and alters glycolysis, a metabolic pathway, in myeloid cells. These findings highlight glycolysis as a potential therapeutic target for the treatment of tuberculosis.
Glycolysis is a metabolic pathway that converts glucose into pyruvate, producing ATP and NADH as energy carriers. The researchers took a selective approach to inhibit glycolytic flux by targeting lactate dehydrogenase (LDH), an enzyme involved in lactate fermentation. They discovered that myeloid cells predominantly express the LDHA subunit of LDH, which converts pyruvate to lactate and NADH to NAD+. LDHA was found to play an important role in the immune response against tuberculosis, as evidenced by its presence in lung tissue from tuberculosis patients.
To further investigate the role of LDHA, the researchers created mice lacking the LDHA subunit in myeloid cells. These mice showed increased susceptibility to M. tuberculosis infection and had a reduced ability to mount an early inflammatory response. Gene expression analysis revealed increased expression of inflammatory process-associated genes, including interferon-gamma, in the lungs of the LDHA-deficient mice. However, bioenergetic experiments demonstrated that LDHA is necessary for macrophages to respond metabolically to interferon-gamma.
Based on the finding that M. tuberculosis depletion of NAD(H) levels disrupts glycolysis, the researchers explored the use of nicotinamide, an NAD+ precursor, as a potential treatment for tuberculosis. In vitro experiments using M. tuberculosis-infected macrophages showed that nicotinamide enhanced glycolysis and reduced bacterial burden. In a mouse model, feeding mice nicotinamide resulted in a significant reduction of M. tuberculosis burden in the lungs.
Nicotinamide was previously studied as a treatment for tuberculosis in the 1940s but fell out of use with the discovery of more effective drugs. However, the current rise in tuberculosis cases and drug resistance has renewed interest in nicotinamide as a potential treatment option. It is inexpensive, orally available, and has a proven safety profile.
The researchers also identified the tuberculosis necrotizing toxin (TNT) as a possible cause of NAD(H) depletion by M. tuberculosis. TNT is the first toxin ever found in this bacterium and significantly reduces NAD+ levels in infected cells.
Further studies are needed to fully understand the mechanisms by which M. tuberculosis disrupts NADH homeostasis and to optimize the use of nicotinamide as a tuberculosis treatment. However, these findings provide valuable insights into the metabolic strategies employed by M. tuberculosis and offer hope for the development of new therapies against this deadly infectious disease.
Frequently Asked Questions (FAQ)
What is tuberculosis?
Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis. It primarily affects the lungs but can also affect other parts of the body, such as the kidneys, spine, and brain. Tuberculosis is transmitted through the air when an infected person coughs, sneezes, or talks.
How does Mycobacterium tuberculosis evade the immune response?
Mycobacterium tuberculosis has evolved various mechanisms to evade the immune response in humans. One of these mechanisms involves perturbing the metabolism of immune cells, particularly myeloid cells. By disrupting a metabolic pathway called glycolysis, the bacterium can hinder the immune system’s ability to eliminate the infection.
What is glycolysis?
Glycolysis is a metabolic pathway that converts glucose into pyruvate, producing energy-rich molecules called ATP and NADH. It is a vital process for the production of energy in cells. However, glycolysis can be manipulated by pathogens like Mycobacterium tuberculosis to alter the immune response.
How is nicotinamide being studied as a tuberculosis treatment?
Nicotinamide, an NAD+ precursor, is being investigated as a potential treatment for tuberculosis. Studies have shown that nicotinamide can enhance glycolysis in infected macrophages and reduce the burden of M. tuberculosis. Its safety, availability, and cost-effectiveness make it an appealing option for further research and development.
What is the significance of this research?
This research provides new insights into the mechanisms by which Mycobacterium tuberculosis evades the immune response and identifies potential therapeutic targets for tuberculosis treatment. Understanding the interactions between the bacterium and the host’s metabolic pathways could lead to the development of innovative strategies to combat this global health threat.
(Source: University of Alabama at Birmingham and Africa Health Research Institute)