New Study Reveals Potential Target for Tuberculosis Treatment

New Study Reveals Potential Target for Tuberculosis Treatment

A recent study conducted by researchers at the University of Alabama in Birmingham and the Africa Health Research Institute sheds light on a potential target for the treatment of tuberculosis (TB). TB is one of the leading infectious disease killers globally, causing 1.6 million deaths in 2021 and 10 million new cases every year.

The study, published in Nature Communications, focuses on the role of glycolysis, a metabolic pathway that converts glucose into pyruvate, in the immune response to Mycobacterium tuberculosis infection. The researchers discovered that M. tuberculosis disrupts the homeostasis of NADH, a high-energy molecule, and reprograms glycolysis in myeloid cells, which include macrophages.

Glycolysis plays an essential role in the immune response by providing energy and high-energy molecules for immune cell function. By targeting glycolysis, researchers aim to develop a therapeutic intervention against M. tuberculosis.

In previous experiments, inhibiting glycolytic flux using a more generalized approach yielded limited success. However, the current study takes a more selective approach by focusing on lactate dehydrogenase (LDH), an enzyme involved in the reversible process of lactate fermentation.

The researchers found that LDHA, a subunit of LDH predominantly expressed in myeloid cells, is essential for the control of M. tuberculosis infection. In mice lacking the LDHA subunit, the glycolytic capacity of myeloid cells was reduced, making them more susceptible to M. tuberculosis infection.

Surprisingly, when the researchers analyzed the gene expression in the lungs of LDHA-deficient mice, they observed an enrichment of mRNAs associated with inflammatory processes. However, these mice had a striking absence of early inflammation in response to M. tuberculosis infection.

To investigate further, the researchers conducted bioenergetics experiments and discovered that LDHA is necessary for the metabolic response of mouse macrophages to interferon-gamma, an antimycobacterial cytokine. This finding suggests that the immune response to M. tuberculosis relies on glycolytic flux in myeloid cells regulated by LDHA.

Based on the depletion of NAD(H) caused by M. tuberculosis, the researchers tested the effects of nicotinamide, an NAD+ precursor, on the immune response. Nicotinamide was found to enhance glycolysis in M. tuberculosis-infected macrophages and reduce the pathogenic burden in vitro and in a mouse model.

The results of this study provide new insights into the metabolic mechanisms employed by M. tuberculosis to evade the immune response. Targeting glycolysis, particularly LDHA, and utilizing nicotinamide as a host-directed therapy could offer a new approach to treating tuberculosis.


What is glycolysis?

Glycolysis is a metabolic pathway that converts glucose into pyruvate while generating high-energy molecules ATP and NADH. It plays a crucial role in providing energy and high-energy molecules for various cellular functions, including the immune response.

What is LDHA?

LDHA is an enzyme called lactate dehydrogenase that catalyzes the reversible conversion of pyruvate to lactate. It consists of subunits, with LDHA predominantly expressed in myeloid cells. LDHA is involved in regulating glycolysis and maintaining the metabolic response of immune cells.

What is nicotinamide?

Nicotinamide is an NAD+ precursor, which means it can be converted into NAD+ in cells. NAD+ plays a crucial role in regulating various cellular processes, including energy metabolism. Nicotinamide has been shown to enhance glycolysis in Mycobacterium tuberculosis-infected macrophages and exhibit efficacy as a treatment for tuberculosis.

How does M. tuberculosis evade the immune response?

M. tuberculosis employs various mechanisms to evade the immune response. In this study, researchers discovered that M. tuberculosis disrupts the host immune response by perturbing the metabolic pathway of glycolysis in myeloid cells. By disrupting glycolysis, the pathogen impairs the ability of immune cells to mount an effective immune response against the infection.

All Rights Reserved 2021.
| .