pubmed.ncbi.nlm.nih.gov

Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy - PubMed

  • ️Wed Jan 01 2020

Review

Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy

Bridgette M Cumming et al. Front Cell Infect Microbiol. 2020.

Abstract

Tuberculosis (TB) was responsible for more deaths in 2019 than any other infectious agent. This epidemic is exacerbated by the ongoing development of multi-drug resistance and HIV co-infection. Recent studies have therefore focused on identifying host-directed therapies (HDTs) that can be used in combination with anti-mycobacterial drugs to shorten the duration of TB treatment and improve TB outcomes. In searching for effective HDTs for TB, studies have looked toward immunometabolism, the study of the role of metabolism in host immunity and, in particular, the Warburg effect. Across a variety of experimental paradigms ranging from in vitro systems to the clinic, studies on the role of the Warburg effect in TB have produced seemingly conflicting results and contradictory conclusions. To reconcile this literature, we take a historical approach to revisit the definition of the Warburg effect, re-examine the foundational papers on the Warburg effect in the cancer field and explore its application to immunometabolism. With a firm context established, we assess the literature investigating metabolism and immunometabolism in TB for sufficient evidence to support the role of the Warburg effect in TB immunity. The effects of the differences between animal models, species of origin of the macrophages, duration of infection and Mycobacterium tuberculosis strains used for these studies are highlighted. In addition, the shortcomings of using 2-deoxyglucose as an inhibitor of glycolysis are discussed. We conclude by proposing experimental criteria that are essential for future studies on the Warburg effect in TB to assist with the research for HDTs to combat TB.

Keywords: Warburg effect; host-directed therapy; immunometabolism; macrophage; tuberculosis.

Copyright © 2020 Cumming, Pacl and Steyn.

PubMed Disclaimer

Figures

Figure 1
Figure 1

Roles of aerobic glycolysis. Aerobic glycolysis generates metabolic intermediates that are used in other biosynthetic pathways such as the pentose phosphate pathway, synthesis of hexosamines, glycerol-3-phosphate for fatty acid synthesis, amino acid synthesis, and one carbon metabolism. Aerobic glycolysis is also involved in maintaining redox balance (NAD+/NADH) in the cell. Inhibition of hexokinase (HK) in the first step of glycolysis by 2-DG will additionally inhibit these pathways and redox homeostasis. Thus, inhibitors reducing the glycolytic flux by acting on enzymes near the end of glycolytic pathway, such as OXA, on LDH, or LDHA knock-out mice will enable a more accurate assessment of the contribution of glycolysis to effector functions of the cell. This figure also demonstrates how both lactate from glycolysis and carbon dioxide generated from mitochondrial metabolism contribute to the acidification of the extracellular environment (ECAR). HK, hexokinase; 2-DG, 2-deoxyglucose; Glc-6-P, glucose-6-phosphate; Fru-6-P, fructose-6-phosphate; PFK, phosphofructokinase, Fru-1,6-biP, fructose-1, 6-bisphosphate; DHAP, dihydroxyacetone phosphate; GAPDH, glyceraldehyde phosphate dehydrogenase, 1,3-bis-PG, 1,3-bisphosphoglycerate; 3-PG, 2-PG, 3- or 2-phosphoglyerate; ENO, enolase; 2-PEP, 2-phosphoenolpyruvate; LDHA, lactate dehydrogenase A; OXA, sodium oxamate; OAA, oxaloacetate; α-KG, α-ketoglutarate.

Similar articles

Cited by

References

    1. Alonso D., Nungester W. J. (1956). Comparative study of host resistance of guinea pigs and rats. V. The effect of pneumococcal products on glycolysis and oxygen uptake by polymorphonuclear leucocytes. J. Infect. Dis. 99, 174–181. 10.1093/infdis/99.2.174 - DOI - PubMed
    1. Aly S., Wagner K., Keller C., Malm S., Malzan A., Brandau S., et al. . (2006). Oxygen status of lung granulomas in Mycobacterium tuberculosis-infected mice. J. Pathol. 210, 298–305. 10.1002/path.2055 - DOI - PubMed
    1. Ast T., Mootha V. K. (2019). Oxygen and mammalian cell culture: are we repeating the experiment of Dr. Ox? Nat. Metab. 1, 858–860. 10.1038/s42255-019-0105-0 - DOI - PubMed
    1. Baay-Guzman G. J., Duran-Padilla M. A., Rangel-Santiago J., Tirado-Rodriguez B., Antonio-Andres G., Barrios-Payan J., et al. . (2018). Dual role of hypoxia-inducible factor 1 alpha in experimental pulmonary tuberculosis: its implication as a new therapeutic target. Future Microbiol. 13, 785–798. 10.2217/fmb-2017-0168 - DOI - PubMed
    1. Bakker A. (1927). Einige übereinstimmungen im stoffwechsel der carcinomzellen und exsudatleukocyten. Klin. Wochenschr. 6, 252–254. 10.1007/BF01710710 - DOI

Publication types

MeSH terms

Substances