Immunometabolism during Mycobacterium tuberculosis Infection

Abstract

Over a quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18% of recurrent cases of TB are multidrug-resistant (MDR) or rifampicin-resistant. Recent evidence has shown that certain drug-resistant strains of Mtb modulate host metabolic reprogramming, and therefore immune responses, during infection. However, it remains unclear how widespread these mechanisms are among circulating MDR Mtb strains and what impact drug-resistance-conferring mutations have on immunometabolism during TB. While few studies have directly addressed metabolic reprogramming in the context of drug-resistant Mtb infection, previous literature examining how drug-resistance mutations alter Mtb physiology and differences in the immune response to drug-resistant Mtb provides significant insights into how drug-resistant strains of Mtb differentially impact immunometabolism.

Keywords: drug resistance; immunometabolism; macrophage metabolism; tuberculosis.

Figure 1.. Drug-Susceptible (DS) Mycobacterium tuberculosis (Mtb) Infection Drives Increased Glycolysis.

DS Mtb infection drives the Warburg effect: increased glycolytic flux driving production of lactate and decreased mitochondrial oxidative metabolism. Following Toll-like receptor (TLR)2 stimulation, increased glycolysis is mediated by upregulation of key genes, including those encoding glucose transporters GLUT1/3/6, although certain genes, like Pfkb3, are differentially regulated by Mtb strains of different lineages. Activation of various pattern-recognition receptors (PRRs) and cytokine receptors drives the induction of the nuclear factor kappa B (NF-κB) pathway, which drives hypoxia inducible factor (HIF-1α) expression, leading to further upregulation of glycolytic genes and the production of critical inflammatory mediators like interleukin (IL)-1β. Sirtuins SIRT1 and SIRT6 downregulate NF-κB and are differentially regulated by Mtb infection. Green indicates upregulation, red indicates downregulation, and purple indicates differential expression that varies between Mtb strains. Abbreviations: IFN, interferon.

Figure 2.. Drug-Susceptible (DS) Mycobacterium tuberculosis (Mtb) Infection Modulates the tricarboxylic acid (TCA) Cycle, Oxidative Phosphorylation (OXPHOS), and Fatty Acid (FA) Metabolism.

While glycolysis is upregulated, the TCA cycle and OXPHOS are downregulated in the acute phase of Mtb infection. Various TCA cycle enzymes are downregulated, including ACO2, isocitrate dehydrogenase 2 (IDH2), and succinate dehydrogenase (SDH), to drive reduced oxidative metabolism. Accumulation of TCA cycle intermediates like citrate and succinate increase the expression and stability of hypoxia inducible factor (HIF)-1α and drives production of the metabolite itaconate. Decreased OXPHOS also drives increased reactive oxygen species (ROS) and reactive nitrogen species (RNS). Acetyl coenzyme-A (Ac-CoA) generated in the mitochondria is converted into the ketone body 3HB rather than fed into the TCA cycle. 3HB signals through GPR109a to drive formation of lipid bodies. Citrate export and the stabilization of HIF-1α may also drive increased lipid droplet (LD) formation. Citrate conversion to Ac-CoA in the cytoplasm feeds into FA metabolism, which is differentially regulated by DS Mtb strains of different lineages. Green indicates upregulation, red indicates downregulation, and purple indicates differential expression that varies between Mtb strains. Abbreviations: AA-CoA, CAC, CIT, FUM, fumarate; α-KG, LXA4, lipoxin A4; NOS2, nitric oxide synthase 2; NOX2, OAA, oxaloacetate; PGE2, prostaglandin E2; SUCC,TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor.

Figure 3.. Drug-Resistant (DR) Mycobacterium tuberculosis (Mtb) Infection Modulates Metabolic Reprogramming.

DR Mtb strains have altered cell wall lipid expression and drive differential immune responses during infection in comparison with drug susceptible (DS) strains. Reduced Toll-like receptor (TLR)2 stimulation by some DR Mtb strains may impair optimal glycolytic flux, although upregulation of ESAT-6 expression by DR Mtb strains may enhance it. Lactate is secreted from the cell as a by-product of aerobic glycolysis; some DR Mtb strains have increased expression of the lldl2 gene that encodes an enzyme that allows Mtb to metabolize lactate as a nutrient source. The increased ratio of interleukin (IL)-10:interferon (IFN)-γ in multidrug-resistant (MDR) tuberculosis (TB) patients may suggest that hypoxia inducible factor (HIF)-1α expression is not strongly upregulated, which correlates with lower IL-1β production during DR Mtb infection. Critical tricarboxylic acid (TCA) cycle enzymes are downregulated by DR Mtb infection, leading to the accumulation of metabolic intermediates and maintaining production of reactive nitrogen species (RNS) and reactive oxygen species (ROS). However, increased induction of immunoregulatory molecules like IL-10 may interfere with RNS/ROS generation and downstream protective inflammatory responses. Lipid droplet (LD) formation may be modulated by altered mycolic acid (MA) expression in the cell wall of DR Mtb, and/or differential induction of tumor necrosis factor (TNF)-α may additionally drive lipid body formation. Green indicates upregulation, red indicates downregulation, and purple indicates differential expression that varies between DR Mtb isolates. Abbreviations: CAC, CIT, FUM, fumarate; IDH2, isocitrate dehydrogenase 2; α-KG, NOS2, nitric oxide synthase 2; NOX2, OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; SDH, succinate dehydrogenase; SUCC, TNFR, tumor necrosis factor receptor.