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

Bridgette M Cumming,Hayden T Pacl,Adrie J C Steyn

doi:10.3389/fcimb.2020.576596

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.

Highlights

There is an unmet need for novel therapeutics against tuberculosis (TB), one of the leading killers among infectious diseases worldwide (WHO, 2019)
In the early 1920’s, Otto Warburg noticed that what set tumor tissue apart from normal tissue is that tumor tissue took up glucose and converted it to lactate in the presence of sufficient oxygen to convert glucose to CO2 (Warburg and Negelein, 1927), a phenomenon later termed the “Warburg effect” (Racker, 1972)
Regardless, major tenants of the field of immunometabolism emerged during this period: exudative leukocytes exhibit robust aerobic glycolysis (Bakker, 1927); myeloid cells, likely neutrophils, are more glycolytic than lymphocytes, likely naïve T cells (Soffer and Wintrobe, 1932); and aerobic glycolysis may be essential for host protection from bacterial infections (Kempner, 1939)

Summary

INTRODUCTION

There is an unmet need for novel therapeutics against tuberculosis (TB), one of the leading killers among infectious diseases worldwide (WHO, 2019). Given that new antimicrobials effective against Mycobacterium tuberculosis (Mtb) are extremely limited, there is great interest in developing host-directed therapies (HDT) to tailor the responses of human cells to treat TB (Wallis and Hafner, 2015; Zumla et al, 2015). The Warburg Effect in Tuberculosis as the Warburg effect, in immune cells have both been described as a potential approach to control Mtb infection, limit tissue damage, or to potentiate existing TB therapies (Shi et al, 2016; Krishnamoorthy et al, 2020). We will review several recent reports that Mtb inhibits glycolysis in infected host cells, highlighting a potential virulence strategy that has only recently been described for this ancient pathogen

BACKGROUND

Findings

CONCLUSION