A breakthrough study conducted by researchers at the University of Alabama in Birmingham and the Africa Health Research Institute sheds light on how Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, disrupts the immune response and perturbs the homeostasis of the high-energy molecule NADH in myeloid cells. This discovery highlights glycolysis, a metabolic pathway responsible for converting glucose into pyruvate, as a potential therapeutic target to combat tuberculosis.
Glycolysis plays a crucial role in the immune response of myeloid cells by providing them with the necessary energy to combat infections. However, M. tuberculosis has evolved a mechanism to interfere with this pathway, impairing the host’s ability to control the infection. The researchers found that the enzyme lactate dehydrogenase, or LDH, which catalyzes the reversible process of lactate fermentation, is predominantly expressed in myeloid cells. When LDH is composed mostly of LDHA subunits, it preferentially converts pyruvate to lactate and NADH to NAD+. On the other hand, an LDH made of LDHB subunits favors the opposite reaction.
By studying lung tissue samples from tuberculosis patients, the researchers discovered that myeloid cells stained positive for LDHA during the immune response in tuberculosis lesions. This implicates LDHA as an important metabolic protein in the immune defense against tuberculosis.
To further investigate the role of LDHA and NADH in tuberculosis pathogenesis, the researchers created mice that lacked the LDHA subunit in myeloid cells. These mice exhibited a reduced glycolytic capacity and were more susceptible to M. tuberculosis infection. The absence of LDHA led to a striking absence of early inflammation, suggesting that LDHA is necessary for protection against tuberculosis.
Interestingly, despite the reduced immune response, gene expression analysis showed that mRNAs associated with inflammatory processes were among the most enriched in the lungs of the LDHA-deficient mice. This conundrum was resolved through bioenergetics experiments that demonstrated the dependence of mouse macrophages on LDHA for their metabolic response to interferon-gamma, a key antimycobacterial cytokine.
Building on these findings, the researchers investigated the potential of nicotinamide, an NAD+ precursor, as a host-directed therapy for tuberculosis. They found that nicotinamide enhanced glycolysis in M. tuberculosis-infected macrophages, resulting in a reduction of the pathogenic bacteria in vitro. In a mouse model, administering nicotinamide for four weeks significantly reduced the M. tuberculosis burden in the lungs and decreased inflammation.
Nicotinamide was originally explored as a treatment for tuberculosis in the 1940s but fell out of use with the discovery of more effective drugs. However, the increasing incidence of tuberculosis and the emergence of drug-resistant strains have renewed interest in nicotinamide as a potential treatment option due to its affordability, safety, tolerability, and oral bioavailability.
While this study provides important insights into the role of glycolysis and LDHA in tuberculosis pathogenesis, a crucial question remains: How does M. tuberculosis deplete NAD(H) levels? Partial explanations include the secretion of tuberculosis necrotizing toxin (TNT) by M. tuberculosis, which acts as an NAD+ glycohydrolase. Further research is needed to fully understand the mechanisms behind NAD(H) depletion and explore potential interventions targeting this process.
Q: What is the role of glycolysis in the immune response against tuberculosis?
A: Glycolysis provides myeloid cells with the energy they need to combat infections, including tuberculosis.
Q: What is LDHA?
A: LDHA is an enzyme involved in lactate fermentation, which is predominantly expressed in myeloid cells and plays a crucial role in their immune function.
Q: How does the absence of LDHA affect the immune response to tuberculosis?
A: Mice lacking the LDHA subunit in myeloid cells exhibit reduced glycolytic capacity and are more susceptible to M. tuberculosis infection. They also show a striking absence of early inflammation.
Q: What is nicotinamide, and how does it affect tuberculosis infection?
A: Nicotinamide is an NAD+ precursor that enhances glycolysis in M. tuberculosis-infected macrophages. It has shown efficacy in reducing the pathogenic bacteria and inflammation associated with tuberculosis.
Q: Why has nicotinamide gained renewed interest as a potential tuberculosis treatment?
A: The increasing incidence of tuberculosis and the emergence of drug-resistant strains have led to a renewed interest in nicotinamide due to its affordability, safety, tolerability, and oral bioavailability.