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

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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.

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Acknowledgments

This work was supported by Cincinnati Children’s Hospital Medical Center Trustee Award, the Division of Infectious Diseases, and the American Heart Association Scientist Development Grant 15SDG21550007 (JEQ) and St. Jude Children’s Research Hospital Cancer Center Core Grant and the American Lebanese Syrian Associated Charities (PJM).

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Correspondence to Joseph E. Qualls or Peter J. Murray.

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This article is a contribution to the Special Issue on Immunopathology of Mycobacterial Diseases - Guest Editor: Stefan Kaufmann

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Qualls, J.E., Murray, P.J. Immunometabolism within the tuberculosis granuloma: amino acids, hypoxia, and cellular respiration. Semin Immunopathol 38, 139–152 (2016). https://doi.org/10.1007/s00281-015-0534-0

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