Abstract
Mycobacterium tuberculosis (Mtb) has complex and intricate interactions with host immune cells. Mtb can survive, persist, and grow within macrophages and thereby circumvent detection by the innate immune system. Recently, the field of immunometabolism, which focuses on the link between metabolism and immune function, has provided us with an improved understanding of the role of metabolism in modulating immune function. For example, host immune cells can switch from oxidative phosphorylation to glycolysis in response to infection, a phenomenon known as the Warburg effect. In this state, immune cells are capable of amplifying production of both antimicrobial pro-inflammatory mediators that are critical for the elimination of bacteria. Also, cells undergoing the Warburg effect upregulate production of nitric oxide augment the synthesis of bioactive lipids. In this review, we describe our current understanding of the Warburg effect and discuss its role in promoting host immune responses to Mtb. In most settings, immune cells utilize the Warburg effect to promote inflammation and thereby eliminate invading bacteria; interestingly, Mtb exploits this effect to promote its own survival. A better understanding of the dynamics of metabolism within immune cells together with the specific features that contribute to the pathogenesis of tuberculosis (TB) may suggest potential host-directed therapeutic targets for promoting clearance of Mtb and limiting its survival in vivo.
Highlights
Tuberculosis (TB) is caused by the pathogenic species, Mycobacterium tuberculosis (Mtb); together with human immunodeficiency virus (HIV/AIDS) infection, TB is among the most prevalent and severe of the infectious diseases worldwide
Immunometabolism is among the critical features that define the intimate relationship between host and the Mtb pathogen; a clear understanding of these interactions will be essential for limiting the progression of the TB
Metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis in Mtb infection results in the upregulated expression of numerous pro-inflammatory cytokines and antimicrobial effector molecules
Summary
Tuberculosis (TB) is caused by the pathogenic species, Mycobacterium tuberculosis (Mtb); together with human immunodeficiency virus (HIV/AIDS) infection, TB is among the most prevalent and severe of the infectious diseases worldwide. Host immune cells responded to Mtb infection with increased expression of pro- inflammatory and antimicrobialrelated genes associated with the Warburg effect These results highlighted the importance of metabolic reprogramming due to glycolysis and its relationship to protection against Mtb infection. Upregulated expression of HIF-1α, the enhanced Warburg effect, and the antimicrobial response to Mtb infection of host immune cells are all linked to the actions of the glycolytic regulatory protein, pyruvate kinase M2 (PKM2). Upregulation of Pkm2/PKM2 was detected in Mtb- infected murine macrophages and in mouse lung tissue [65] These results suggest that, similar to itaconate, PKM2 promotes the HIF-1α-mediated Warburg effect and the associated antimicrobial response during Mtb infection. The HIF-1α induced Warburg effect in the setting of TB infection plays an essential role in promoting upregulation of pro-inflammatory cytokine and antimicrobial effector gene expression, both factors underlying the acute immune response. AMPK and other metabolic energy sensors are critical in maintaining various functions of Mtb-infected host immune cells, including autophagy, fatty acid β- oxidation, and metabolic reprogramming; the AMPK pathway plays multi-faceted
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