Immunometabolism within the tuberculosis granuloma: amino acids, hypoxia, and cellular respiration

Abstract

Tuberculosis (TB) granulomas are compact, organized agglomerations of infected and uninfected macrophages, T cells, neutrophils, and other immune cells. Within the granuloma, several unique metabolic adaptations occur to modify the behavior of immune cells, potentially favoring bacterial persistence balanced with protection against immunopathology. These include the induction of arginase-1 in macrophages to temper nitric oxide (NO) production and block T cell proliferation, inhibition of oxygen-requiring NO production in hypoxic regions, and induction of tryptophan-degrading enzymes that modify T cell proliferation and function. The spatial and time-dependent organization of granulomas further influences immunometabolism, for example through lactate production by activated macrophages, which can induce arginase-1. Although complex, the metabolic changes in and around TB granulomas can be potentially modified by host-directed therapies. While elimination of the TB bacilli is often the goal of any anti-TB therapy, host-directed approaches must also account for the possibility of immunopathologic damage to the lung.

Keywords: Granuloma; Hypoxia; L-arginine; L-tryptophan; Metabolism; Tuberculosis.

Fig. 1. Nutrition and metabolism in tuberculosis granulomas

The tuberculosis granuloma response balances immune-mediated protection and tissue pathology in many ways, including amino acid regulation, hypoxia, and other metabolism alterations.

Fig. 2. Amino acid metabolism in immune cells

A) L-arginine metabolism. B) L-tryptophan metabolism. Abbreviations: iNOS, inducible nitric oxide synthase; Arg, arginase; Ass1; argininosuccinate synthase; Asl, argininosuccinate lyase; IDO, indoleamine 2,3-dioxygenase; Afmid, kynurenine formamidase.

Fig. 3. Altered microbicidal agent production and metabolism in hypoxic microenvironments

A) ROS and RNS production in cells within tuberculosis granulomas become less efficient approaching areas of hypoxia. B) Anaerobic glycolysis dominates glucose metabolism in hypoxic microenvironments, leading to lactate production and downstream effectors triggered by lactate (e.g. Arg1). Abbreviations: SOD, superoxide dismutase; MPO, myeloperoxidase.