The Link between Glycolysis and Tuberculosis: Targeting a Metabolic Pathway for Treatment

The Link between Glycolysis and Tuberculosis: Targeting a Metabolic Pathway for Treatment

Tuberculosis, the leading infectious disease worldwide, claims the lives of 1.6 million people annually and results in 10 million new cases each year. Until now, the exact mechanisms used by Mycobacterium tuberculosis to evade the human immune response have remained uncertain. Recent evidence suggests that the disruption of host immunometabolism, the connection between metabolism in immune cells and their immune function, may play a crucial role.

A group of researchers from the University of Alabama in Birmingham and the Africa Health Research Institute conducted a study, published in Nature Communications, that sheds light on how M. tuberculosis manipulates the metabolism of myeloid cells. Their findings highlight glycolysis, a metabolic pathway that converts glucose into energy-rich molecules, as a potential target for therapeutic intervention against the deadly infectious disease.

The study revealed that M. tuberculosis disturbs the balance of a high-energy molecule called NADH and reprograms glycolysis in myeloid cells. By selectively inhibiting glycolytic flux, researchers were able to weaken the pathogen’s impact. Previous approaches had taken a broad approach, obstructing glucose uptake in myeloid cells, but this new method provides a more targeted solution.

Another vital discovery was the role of lactate dehydrogenase (LDH), an enzyme responsible for catalyzing the reversible process of lactate fermentation. When LDH is predominantly composed of LDHA subunits, which are found in myeloid cells, it converts pyruvate to lactate and NADH to NAD+. Conversely, an LDH made of LDHB subunits favors the opposite reaction.

The researchers further analyzed lung tissue from tuberculosis patients and found that LDHA played an essential role in the immune response within the lesions. It appeared to protect against tuberculosis by regulating glycolytic flux in myeloid cells. To confirm this, the team created mice that lacked the LDHA subunit and observed increased susceptibility to infection and reduced survival time.

Despite the LDHA-deficient mice exhibiting a blunted immune response, gene expression analysis showed a notable presence of mRNAs associated with inflammation. This intriguing finding led to bioenergetics experiments that highlighted the necessity of LDHA and its role in metabolically responding to interferon-gamma, a critical antimycobacterial cytokine.

Building upon the central role of NADH in glycolytic inhibition caused by M. tuberculosis, researchers investigated the potential of nicotinamide, an NAD+ precursor, as a host-directed therapy. They discovered that nicotinamide enhanced glycolysis in infected macrophages, reducing the pathogenic bacterial burden both in vitro and in a mouse model.

Although nicotinamide was first explored as a tuberculosis treatment in the 1940s, subsequent discoveries rendered it obsolete. However, the evolving landscape of tuberculosis, with increasing incidence and drug resistance, has reopened the possibility of repurposing this inexpensive, safe, and widely available compound.

This study has provided valuable insights into the crucial interaction between glycolysis and tuberculosis. By identifying metabolic vulnerabilities in M. tuberculosis and manipulating them through targeted interventions, researchers are paving the way for potential breakthroughs in tuberculosis treatment.

Frequently Asked Questions (FAQ)

  1. What is tuberculosis?
  2. Tuberculosis is an infectious disease caused by the bacteria Mycobacterium tuberculosis. It primarily affects the lungs but can also spread to other parts of the body.

  3. How many people are affected by tuberculosis?
  4. Tuberculosis claims the lives of 1.6 million individuals annually and results in 10 million new cases each year.

  5. What is glycolysis?
  6. Glycolysis is a metabolic pathway that converts glucose into pyruvate, generating high-energy molecules such as ATP and NADH.

  7. Why is glycolysis important in tuberculosis?
  8. The study suggests that manipulating glycolysis, a metabolic pathway disrupted by M. tuberculosis, can offer therapeutic targets to combat the disease.

  9. What is nicotinamide, and how does it relate to tuberculosis treatment?
  10. Nicotinamide is an NAD+ precursor that enhances glycolysis in M. tuberculosis-infected macrophages. It has demonstrated efficacy in reducing the pathogenic burden and inflammation associated with tuberculosis.


* Nature Communications: [insert URL]

* University of Alabama in Birmingham: [insert URL]

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