A recent study conducted by researchers at the University of Alabama in Birmingham and the Africa Health Research Institute has shed light on how Mycobacterium tuberculosis, the world’s leading infectious disease killer, affects the immune response in humans. Tuberculosis caused 1.6 million deaths in 2021, with 10 million new cases reported each year.
The researchers discovered that M. tuberculosis disrupts the balance of the high-energy molecule NADH and reprograms glycolysis in myeloid cells, which include macrophages. Glycolysis is a metabolic pathway that converts glucose into pyruvate, generating ATP and NADH. By understanding this mechanism, scientists hope to find a potential therapeutic target for tackling tuberculosis.
The study showed that inhibiting glycolytic flux selectively could be more effective in combating the pathogen compared to previous approaches. Previous experiments focused on blocking glucose uptake into myeloid cells using inhibitors. In contrast, the researchers used a more specific approach by targeting lactate fermentation, catalyzed by the enzyme lactate dehydrogenase (LDH). They found that LDHA, a subunit of LDH mostly expressed in myeloid cells, plays a crucial role in the immune response to tuberculosis.
To test their hypothesis, the researchers created mice lacking the LDHA subunit in myeloid cells. These mice exhibited reduced glycolytic capacity, making them more susceptible to M. tuberculosis infection and demonstrating worse lung pathology. This suggests that LDHA and glycolytic flux in myeloid cells are essential for protecting against tuberculosis and controlling the infection.
Surprisingly, despite the reduced immune response, gene expression analysis revealed that certain mRNAs associated with inflammation, particularly interferon-gamma, were enriched in the LDHA-deficient mice. Further experiments showed that interferon-gamma’s antimycobacterial cytokine response required LDHA and its NAD+ regeneration mediated by LDH.
The study also explored the potential use of nicotinamide, an NAD+ precursor, as a host-directed therapy to enhance glycolysis in M. tuberculosis-infected macrophages. Nicotinamide increased glycolytic capacity and reduced the burden of the pathogen in both in vitro experiments and a mouse model.
Although nicotinamide was once considered a treatment for tuberculosis in the past, it fell out of favor due to the discovery of more effective drugs. However, with the current increase in tuberculosis cases and drug resistance, nicotinamide could be a promising candidate due to its affordability, oral availability, safety, and tolerability.
As the researchers continue to investigate the mechanisms through which M. tuberculosis depletes NAD(H) levels, this study provides valuable insights into potential therapeutic strategies against tuberculosis.
What is tuberculosis?
Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis, resulting in severe lung infections. It is one of the deadliest infectious diseases globally.
How many deaths does tuberculosis cause annually?
Tuberculosis caused 1.6 million deaths in 2021 and continues to be a significant public health concern worldwide.
What is glycolysis?
Glycolysis is a metabolic pathway that converts glucose into pyruvate, producing ATP (adenosine triphosphate) and NADH (nicotinamide adenine dinucleotide).
What is LDHA?
LDHA is a subunit of the enzyme lactate dehydrogenase (LDH). It plays a crucial role in the metabolism of myeloid cells and their immune response.
What is nicotinamide?
Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD+), an essential molecule involved in various metabolic processes. In the context of the study, nicotinamide was explored as a potential host-directed therapy for tuberculosis.