A recent study conducted by researchers at the University of Alabama in Birmingham and the Africa Health Research Institute (AHRI) has shed light on the mechanism through which Mycobacterium tuberculosis evades the immune response in humans. By disrupting the glycolysis pathway in infected myeloid cells, the pathogen effectively deflects the immune system. This new understanding presents an opportunity for developing targeted therapies against the bacterium, which caused 1.6 million deaths in 2021 and continues to be a major global health concern.
Glycolysis is a metabolic pathway that converts glucose into pyruvate, producing adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH) as high-energy molecules. The researchers found that M. tuberculosis reprograms this pathway and disrupts the homeostasis of NADH in myeloid cells. This discovery highlights glycolysis as a potential therapeutic target in the fight against tuberculosis, the leading infectious disease killer worldwide.
Unlike previous approaches that have used inhibitors to block glucose uptake into myeloid cells, the researchers took a more selective approach. They focused on lactate dehydrogenase (LDH), an enzyme responsible for the reversible process of lactate fermentation, which is a key step in glycolysis. LDH has two subunits, LDHA and LDHB, with LDHA being predominantly expressed in myeloid cells. The study found that LDHA plays a critical role in tuberculosis pathogenesis. Lung tissue samples from tuberculosis patients showed positive staining for LDHA in myeloid cells, bronchial epithelial cells, and lymphocytes involved in granuloma formation and alveolitis.
These findings provide valuable insights into the metabolic changes induced by M. tuberculosis and its impact on the immune response in tuberculosis lesions. Targeting LDHA and glycolysis could offer a novel therapeutic strategy to combat tuberculosis. Future studies will aim to develop specific inhibitors or interventions that can modulate LDHA activity and restore immune function. By unraveling the intricate link between immunometabolism and tuberculosis pathogenesis, researchers are paving the way for advancements in tuberculosis treatment and prevention.
What is tuberculosis?
Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis. It primarily affects the lungs but can also affect other parts of the body. TB is spread through the air when an infected individual coughs or sneezes, making it highly contagious.
What is glycolysis?
Glycolysis is a metabolic pathway that breaks down glucose to produce energy in the form of adenosine triphosphate (ATP) and other intermediates. It is a fundamental process in cellular metabolism and is essential for various cellular functions.
What is lactate dehydrogenase (LDH)?
Lactate dehydrogenase (LDH) is an enzyme involved in the reversible conversion of pyruvate to lactate as part of lactate fermentation. LDH plays a crucial role in energy production and is essential for maintaining the balance of metabolites involved in glycolysis.
How can targeting LDHA help in tuberculosis treatment?
The study revealed that LDHA is prominently expressed in myeloid cells, which are targeted by M. tuberculosis. By understanding how the pathogen disrupts glycolysis and reprograms NADH homeostasis, researchers can explore the possibility of developing specific inhibitors or interventions to modulate LDHA activity. This approach could potentially restore immune function and provide a new therapeutic strategy against tuberculosis.