Therapeutic Potentials of Immunometabolomic Modulations Induced by Tuberculosis Vaccination

Abstract

Metabolomics is emerging as a promising tool to understand the effect of immunometabolism for the development of novel host-directed alternative therapies. Immunometabolism can modulate both innate and adaptive immunity in response to pathogens and vaccinations. For instance, infections can affect lipid and amino acid metabolism while vaccines can trigger bile acid and carbohydrate pathways. Metabolomics as a vaccinomics tool, can provide a broader picture of vaccine-induced biochemical changes and pave a path to potentiate the vaccine efficacy. Its integration with other systems biology tools or treatment modes can enhance the cure, response rate, and control over the emergence of drug-resistant strains. Mycobacterium tuberculosis (Mtb) infection can remodel the host metabolism for its survival, while there are many biochemical pathways that the host adjusts to combat the infection. Similarly, the anti-TB vaccine, Bacillus Calmette-Guerin (BCG), was also found to affect the host metabolic pathways thus modulating immune responses. In this review, we highlight the metabolomic schema of the anti-TB vaccine and its therapeutic applications. Rewiring of immune metabolism upon BCG vaccination induces different signaling pathways which lead to epigenetic modifications underlying trained immunity. Metabolic pathways such as glycolysis, central carbon metabolism, and cholesterol synthesis play an important role in these aspects of immunity. Trained immunity and its applications are increasing day by day and it can be used to develop the next generation of vaccines to treat various other infections and orphan diseases. Our goal is to provide fresh insight into this direction and connect various dots to develop a conceptual framework.

Keywords: Bacillus Calmette-Guerin; Mycobacterium tuberculosis; epigenetics and immunity; immunometabolism; metabolomics; trained immunity; tuberculosis; vaccine metabolism; vaccinomics.

Figure 1

Analyzing Immunometabolomic effects of TB vaccination. In a clinical setup, body fluids (such as blood serum or plasma and urine) would be collected and processed to run on a GC-MS or LC-MS to profile the levels of the metabolites and then analyzed various bioinformatic tools. Quantitative analysis shows the changes in different pathways as compared to placebo subjects. A correlation has been shown between metabolic remodeling, trained immunity, and epigenetics. These may potentiate the effect of the vaccine to mount a better immune response. (Abbreviations: GC-MS: Gas chromatography-mass spectrometry, LC-MS: Liquid chromatography-mass spectrometry.) (The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license).

Figure 2

Mechanism of BCG-induced metabolic reprogramming and its role in the activation of trained immunity through epigenetic modifications of histones. BCG stimulates innate immune cells such as naïve monocytes, macrophages, and natural killer (NK) cells. Phagolysosomal digestion of BCG induces PI3/Akt and mTOR signaling pathways which directly affect the expression of HIF1α thus modifying the glycolysis and the TCA cycle. Acetyl-CoA (Ac.CoA), fumarate, and succinate can affect the activity of HATs and KDMs and induce epigenetic modifications of histones. These modifications of histones result in better access to promoters of proinflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) and program immune cells for the next encounter. Booster or second exposure results in an excessive amount of cytokines and activation of different markers (TLR4, CD11b, and CD14). This trained immunity can protect against many diseases like sepsis, type 1 diabetes mellitus, pneumonia, asthma, allergic rhinitis, melanoma, etc. (Abbreviations: BCG: Bacillus Calmette-Guérin, PI3: Phosphatidylinositol 3-kinase, Akt: Serine/Threonine protein kinase B, mTOR: mammalian Target of Rapamycin, HIF1α: Hypoxia Inducible Factor 1 Subunit Alpha, ATP: Adenosine triphosphate, TCA: Tricarboxylic Acid cycle, IL-1β: Interleukin-1 beta, IL-6: Interleukin 6, TNF-α: Tumor necrosis factor alpha, TLR4: Toll-Like Receptor 4, CD11b: Cluster of Differentiation molecule 11B, CD14: Cluster of Differentiation 14, 2DG: 2-Deoxy-d-glucose, Ac.CoA: Acetyl coenzyme A, Me: Methylation, HAT: Histone Acetyltransferases, KDMs: Lysine Demethylases.) (The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.).