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.
Similar content being viewed by others
References
Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL (2014) Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin Immunol 26(6):454–470. doi:10.1016/j.smim.2014.09.008
Orme IM, Robinson RT, Cooper AM (2015) The balance between protective and pathogenic immune responses in the TB-infected lung. Nat Immunol 16(1):57–63. doi:10.1038/ni.3048
Das B, Kashino SS, Pulu I, Kalita D, Swami V, Yeger H, Felsher DW, Campos-Neto A (2013) CD271(+) bone marrow mesenchy-mal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl Med 5(170):170ra113. doi:10.1126/ scitranslmed.3004912
Panjabi R, Comstock GW, Golub JE (2007) Recurrent tuberculosis and its risk factors: adequately treated patients are still at high risk. Int J Tuberc Lung Dis 11(8):828–837
Wallis RS, Hafner R (2015) Advancing host-directed therapy for tuberculosis. Nat Rev Immunol 15(4):255–263. doi:10.1038/ nri3813
Norata GD, Caligiuri G, Chavakis T, Matarese G, Netea MG, Nicoletti A, O’Neill LA, Marelli-Berg FM (2015) The cellular and molecular basis of translational immunometabolism. Immunity 43(3):421–434. doi:10.1016/j.immuni.2015.08.023
Dorhoi A, Kaufmann SH (2014) Perspectives on host adaptation in response to Mycobacterium tuberculosis: modulation of inflammation. Semin Immunol 26(6):533–542. doi:10.1016/j.smim. 2014.10.002
Cooper AM, Torrado E (2012) Protection versus pathology in tuberculosis: recent insights. Curr Opin Immunol 24(4):431–437. doi:10.1016/j.coi.2012.04.008
Gideon HP, Phuah J, Myers AJ, Bryson BD, Rodgers MA, Coleman MT, Maiello P, Rutledge T, Marino S, Fortune SM, Kirschner DE, Lin PL, Flynn JL (2015) Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization. PLoS Pathog 11(1):e1004603. doi:10.1371/journal.ppat.1004603
Lin PL, Coleman T, Carney JP, Lopresti BJ, Tomko J, Fillmore D, Dartois V, Scanga C, Frye LJ, Janssen C, Klein E, Barry CE 3rd, Flynn JL (2013) Radiologic responses in cynomolgous macaques for assessing tuberculosis chemotherapy regimens. Antimicrob Agents Chemother. doi:10.1128/AAC.00277-13
Ramakrishnan L (2012) Revisiting the role of the granuloma intuberculosis. Nat Rev Immunol 12(5):352–366. doi:10.1038/ nri3211
Young D (2009) Animal models of tuberculosis. Eur J Immunol 39(8):2011–2014. doi:10.1002/eji.200939542
Orme IM, Basaraba RJ (2014) The formation of the granuloma in tuberculosis infection. Semin Immunol 26(6):601–609. doi:10.1016/j.smim.2014.09.009
Dharmadhikari AS, Nardell EA (2008) What animal models teach humans about tuberculosis. Am J Respir Cell Mol Biol 39(5):503–508. doi:10.1165/rcmb.2008-0154TR
Gupta UD, Katoch VM (2005) Animal models of tuberculosis. Tuberculosis (Edinb) 85(5-6):277–293. doi:10.1016/j.tube.2005.08.008
Dorhoi A, Reece ST, Kaufmann SH (2011) For better or for worse: the immune response against Mycobacterium tuberculosis balances pathology and protection. Immunol Rev 240(1):235–251. doi:10.1111/j.1600-065X.2010.00994.x
Cooper AM, Dalton DK, Stewart TA, Griffin JP, Russell DG, Orme IM (1993) Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med 178(6):2243–2247
Duque-Correa MA, Kuhl AA, Rodriguez PC, Zedler U, Schommer-Leitner S, Rao M, Weiner J 3rd, Hurwitz R, Qualls JE, Kosmiadi GA, Murray PJ, Kaufmann SH, Reece ST (2014) Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas. Proc Natl Acad Sci U S A 111(38):E4024–4032. doi:10.1073/pnas.1408839111
Reece ST, Loddenkemper C, Askew DJ, Zedler U, Schommer-Leitner S, Stein M, Mir FA, Dorhoi A, Mollenkopf HJ, Silverman GA, Kaufmann SH (2010) Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice. J Clin Invest 120(9):3365–3376. doi:10.1172/JCI42796
Cooper AM, Pearl JE, Brooks JV, Ehlers S, Orme IM (2000) Expression of the nitric oxide synthase 2 gene is not essential for early control of Mycobacterium tuberculosis in the murine lung. Infect Immun 68(12):6879–6882
Dutta NK, Illei PB, Jain SK, Karakousis PC (2014) Characterization of a novel necrotic granuloma model of latent tuberculosis infection and reactivation in mice. Am J Pathol 184(7):2045–2055. doi:10.1016/j.ajpath.2014.03.008
Harper J, Skerry C, Davis SL, Tasneen R, Weir M, Kramnik I, Bishai WR, Pomper MG, Nuermberger EL, Jain SK (2012) Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions. J Infect Dis 205(4):595–602. doi:10.1093/infdis/jir786
Pan H, Yan BS, Rojas M, Shebzukhov YV, Zhou H, Kobzik L, Higgins DE, Daly MJ, Bloom BR, Kramnik I (2005) Ipr1 gene mediates innate immunity to tuberculosis. Nature 434(7034):767–772. doi:10.1038/nature03419
Calderon VE, Valbuena G, Goez Y, Judy BM, Huante MB, Sutjita P, Johnston RK, Estes DM, Hunter RL, Actor JK, Cirillo JD, Endsley JJ (2013) A humanized mouse model of tuberculosis. PLoS One 8(5):e63331. doi:10.1371/journal. pone.0063331
Cyktor JC, Carruthers B, Kominsky RA, Beamer GL, Stromberg P, Turner J (2013) IL-10 inhibits mature fibrotic granuloma formation during Mycobacterium tuberculosis infection. J Immunol 190(6):2778–2790. doi:10.4049/ jimmunol.1202722
Li P, Yin YL, Li D, Kim SW, Wu G (2007) Amino acids and immune function. Br J Nutr 98(2):237–252. doi:10.1017/ S000711450769936X
Morris SM Jr (2007) Arginine metabolism: boundaries of our knowledge. J Nutr 137(6 Suppl 2):1602S–1609S
Batshaw ML, Tuchman M, Summar M, Seminara J, Members of the Urea Cycle Disorders C (2014) A longitudinal study of urea cycle disorders. Mol Genet Metab 113(1-2):127–130. doi:10.1016/j.ymgme.2014.08.001
Rauch I, Muller M, Decker T (2013) The regulation of inflammation by interferons and their STATs. JAKSTAT 2(1):e23820. doi:10.4161/jkst.23820
MacMicking J, Xie QW, Nathan C (1997) Nitric oxide and macrophage function. Annu Rev Immunol 15:323–350. doi:10.1146/ annurev.immunol.15.1.323
MacMicking JD, North RJ, LaCourse R, Mudgett JS, Shah SK, Nathan CF (1997) Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci U S A 94(10):5243–5248
Garcia I, Guler R, Vesin D, Olleros ML, Vassalli P, Chvatchko Y, Jacobs M, Ryffel B (2000) Lethal Mycobacterium bovis Bacillus Calmette Guerin infection in nitric oxide synthase 2deficient mice: cell-mediated immunity requires nitric oxide synthase 2. Lab Investig 80(9):1385–1397
Bogdan C (2015) Nitric oxide synthase in innate and adaptive immunity: an update. Trends Immunol 36(3):161–178. doi:10.1016/j.it.2015.01.003
Mattila JT, Ojo OO, Kepka-Lenhart D, Marino S, Kim JH, Eum SY, Via LE, Barry CE 3rd, Klein E, Kirschner DE, Morris SM Jr, Lin PL, Flynn JL (2013) Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol 191(2):773–784. doi:10.4049/jimmunol.1300113
Pessanha AP, Martins RA, Mattos-Guaraldi AL, Vianna A, Moreira LO (2012) Arginase-1 expression in granulomas of tu-berculosis patients. FEMS Immunol Med Microbiol 66(2):265–268. doi:10.1111/j.1574-695X.2012.01012.x
Qualls JE, Neale G, Smith AM, Koo MS, DeFreitas AA, Zhang H, Kaplan G, Watowich SS, Murray PJ (2010) Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling. Sci Signal 3(135):ra62. doi:10.1126/scisignal.2000955
Shi O, Morris SM Jr, Zoghbi H, Porter CW, O’Brien WE (2001) Generation of a mouse model for arginase II deficiency by targeted disruption of the arginase II gene. Mol Cell Biol 21(3):811–813. doi:10.1128/MCB.21.3.811-813.2001
Mills CD (2012) M1 and M2 macrophages: oracles of health anddisease. Crit Rev Immunol 32(6):463–488
Mills CD (2015) Anatomy of a discovery: m1 and m2 macro-phages. Front Immunol 6:212. doi:10.3389/fimmu.2015.00212
Mills CD, Ley K (2014) M1 and M2 macrophages: the chicken and the egg of immunity. J Innate Immun 6(6):716–726. doi:10.1159/000364945
El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, Konig T, Schleicher U, Koo MS, Kaplan G, Fitzgerald KA, Tuomanen EI, Orme IM, Kanneganti TD, Bogdan C, Wynn TA, Murray PJ (2008) Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9(12):1399–1406. doi:10.1038/ni.1671
Thomas AC, Mattila JT (2014) BOf mice and men^: arginine metabolism in macrophages. Front Immunol 5:479. doi:10.3389/ fimmu.2014.00479
Azad AK, Sadee W, Schlesinger LS (2012) Innate immune gene polymorphisms in tuberculosis. Infect Immun 80(10):3343–3359. doi:10.1128/IAI.00443-12
Choi HS, Rai PR, Chu HW, Cool C, Chan ED (2002) Analysis of nitric oxide synthase and nitrotyrosine expression in human pulmonary tuberculosis. Am J Respir Crit Care Med 166(2):178–186
Jagannath C, Actor JK, Hunter RL Jr (1998) Induction of nitric oxide in human monocytes and monocyte cell lines by Mycobacterium tuberculosis. Nitric Oxide 2(3):174–186. doi:10.1006/niox.1998.9999
Nicholson S, Bonecini-Almeida Mda G, Silva JR LE, Nathan C, Xie QW, Mumford R, Weidner JR, Calaycay J, Geng J, Boechat N, Linhares C, Rom W, Ho JL (1996) Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med 183(5):2293–2302
Ralph AP, Yeo TW, Salome CM, Waramori G, Pontororing GJ, Kenangalem E, Sandjaja TE, Lumb R, Maguire GP, Price RN, Chatfield MD, Kelly PM, Anstey NM (2013) Impaired pulmonary nitric oxide bioavailability in pulmonary tuberculosis: association with disease severity and delayed mycobacterial clearance with treatment. J Infect Dis 208(4):616–626. doi:10.1093/infdis/jit248
Rich EA, Torres M, Sada E, Finegan CK, Hamilton BD, Toossi Z (1997) Mycobacterium tuberculosis (MTB)-stimulated production of nitric oxide by human alveolar macrophages and relationship of nitric oxide production to growth inhibition of MTB. Tuber Lung Dis 78(5-6):247–255
Wang CH, Liu CY, Lin HC, Yu CT, Chung KF, Kuo HP (1998) Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages. Eur Respir J 11(4):809–815
Brooks MN, Rajaram MV, Azad AK, Amer AO, Valdivia-Arenas MA, Park JH, Nunez G, Schlesinger LS (2011) NOD2 controls the nature of the inflammatory response and subsequent fate of Mycobacterium tuberculosis and M. bovis BCG in human macrophages. Cell Microbiol 13(3):402. doi:10.1111/j.1462-5822. 2010.01544.x
Juarez E, Carranza C, Hernandez-Sanchez F, Leon-Contreras JC, Hernandez-Pando R, Escobedo D, Torres M, Sada E (2012) NOD2 enhances the innate response of alveolar macrophages to Mycobacterium tuberculosis in humans. Eur J Immunol 42(4):880–889. doi:10.1002/eji.201142105
Divangahi M, Mostowy S, Coulombe F, Kozak R, Guillot L, Veyrier F, Kobayashi KS, Flavell RA, Gros P, Behr MA (2008) NOD2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity. J Immunol 181(10):7157–7165
Gandotra S, Jang S, Murray PJ, Salgame P, Ehrt S (2007) Nucleotide-binding oligomerization domain protein 2-deficient mice control infection with Mycobacterium tuberculosis. Infect Immun 75(11):5127–5134. doi:10.1128/IAI.00458-07
Austin CM, Ma X, Graviss EA (2008) Common nonsynonymous polymorphisms in the NOD2 gene are associated with resistance or susceptibility to tuberculosis disease in African Americans. J Infect Dis 197(12):1713–1716. doi:10.1086/588384
Pan H, Ping XC, Zhu HJ, Gong FY, Dong CX, Li NS, Wang LJ, Yang HB (2011) Association of myostatin gene polymorphisms with obesity in Chinese north Han human subjects. Gene 494(2):237–241. doi:10.1016/j.gene.2011.10.045
Wang C, Chen ZL, Pan ZF, Wei LL, Xu DD, Jiang TT, Zhang X, Ping ZP, Li ZJ, Li JC (2013) NOD2 polymorphisms and pulmonary tuberculosis susceptibility: a systematic review and meta-analysis. Int J Biol Sci 10(1):103–108. doi:10.7150/ijbs.7585
Zhao M, Jiang F, Zhang W, Li F, Wei L, Liu J, Xue Y, Deng X, Wu F, Zhang L, Zhang X, Zhang Y, Fan D, Sun X, Jiang T, Li JC (2012) A novel single nucleotide polymorphism within the NOD2 gene is associated with pulmonary tuberculosis in the Chinese Han, Uygur and Kazak populations. BMC Infect Dis 12:91. doi:10.1186/1471-2334-12-91
Landes MB, Rajaram MV, Nguyen H, Schlesinger LS (2015) Role for NOD2 in Mycobacterium tuberculosis-induced iNOS expression and NO production in human macrophages. J Leukoc Biol 97(6):1111–1119. doi:10.1189/jlb.3A1114-557R
Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3(1):23–35. doi:10.1038/nri978
Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604. doi:10.1016/j.immuni.2010.05.007
Rook GA, Hernandez-Pando R, Dheda K, Teng Seah G (2004) IL-4 in tuberculosis: implications for vaccine design. Trends Immunol 25(9):483–488. doi:10.1016/j.it.2004.06.005
van Crevel R, Karyadi E, Preyers F, Leenders M, Kullberg BJ, Nelwan RH, van der Meer JW (2000) Increased production of interleukin 4 by CD4+ and CD8+ T cells from patients with tuberculosis is related to the presence of pulmonary cavities. J Infect Dis 181(3):1194–1197. doi:10.1086/315325
Ashenafi S, Aderaye G, Bekele A, Zewdie M, Aseffa G, Hoang AT, Carow B, Habtamu M, Wijkander M, Rottenberg M, Aseffa A, Andersson J, Svensson M, Brighenti S (2014) Progression of clinical tuberculosis is associated with a Th2 immune response signature in combination with elevated levels of SOCS3. Clin Immunol 151(2):84–99. doi:10.1016/j.clim.2014.01.010
Heitmann L, Abad Dar M, Schreiber T, Erdmann H, Behrends J, McKenzie AN, Brombacher F, Ehlers S, Holscher C (2014) The IL-13/IL-4Ralpha axis is involved in tuberculosis-associated pathology. J Pathol 234(3):338–350. doi:10.1002/path.4399
Guler R, Parihar SP, Savvi S, Logan E, Schwegmann A, Roy S, Nieuwenhuizen NE, Ozturk M, Schmeier S, Suzuki H, Brombacher F (2015) IL-4Ralpha-dependent alternative activation of macrophages is not decisive for Mycobacterium tuberculosis pathology and bacterial burden in mice. PLoS One 10(3):e0121070. doi:10.1371/journal.pone.0121070
Munder M, Schneider H, Luckner C, Giese T, Langhans CD, Fuentes JM, Kropf P, Mueller I, Kolb A, Modolell M, Ho AD (2006) Suppression of T-cell functions by human granulocyte arginase. Blood 108(5):1627–1634. doi:10.1182/blood-2006-11-010389
Qualls JE, Subramanian C, Rafi W, Smith AM, Balouzian L, DeFreitas AA, Shirey KA, Reutterer B, Kernbauer E, Stockinger S, Decker T, Miyairi I, Vogel SN, Salgame P, Rock CO, Murray PJ (2012) Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. Cell Host Microbe 12(3):313–323. doi:10.1016/j.chom.2012.07.012
Hibbs JB Jr, Taintor RR, Vavrin Z, Rachlin EM (1988) Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 157(1):87–94
Benninghoff B, Lehmann V, Eck HP, Droge W (1991) Production of citrulline and ornithine by interferon-gamma treated macrophages. Int Immunol 3(5):413–417
Bansal V, Rodriguez P, Wu G, Eichler DC, Zabaleta J, Taheri F, Ochoa JB (2004) Citrulline can preserve proliferation and prevent the loss of CD3 zeta chain under conditions of low arginine. JPEN J Parenter Enteral Nutr 28(6):423–430
Rodriguez PC, Quiceno DG, Ochoa AC (2007) L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109(4):1568–1573. doi:10.1182/blood-2006-06-031856
Tarasenko TN, Gomez-Rodriguez J, McGuire PJ (2015) Impaired T cell function in argininosuccinate synthetase deficiency. J Leukoc Biol 97(2):273–278. doi:10.1189/jlb.1AB0714-365R
Rapovy SM, Zhao J, Bricker RL, Schmidt SM, Setchell KD, Qualls JE (2015) Differential requirements for L-citrulline and L-arginine during antimycobacterial macrophage activity. J Immunol. doi:10.4049/jimmunol.1500800
Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, Smith AM, Thompson RW, Cheever AW, Murray PJ, Wynn TA (2009) Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 5(4):e1000371. doi:10.1371/journal.ppat.1000371
Obregon-Henao A, Henao-Tamayo M, Orme IM, Ordway DJ (2013) Gr1(int)CD11b + myeloid-derived suppressor cells in Mycobacterium tuberculosis infection. PLoS One 8(11):e80669. doi:10.1371/journal.pone.0080669
Le Floc’h N, Otten W, Merlot E (2011) Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids 41(5):1195–1205. doi:10.1007/s00726-010-0752-7
Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189(9):1363–1372
Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, Mellor AL (2002) Tryptophan deprivation sensitizes activated T cells to apo-ptosis prior to cell division. Immunology 107(4):452–460
Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, Fioretti MC, Puccetti P (2002) T cell apoptosis by tryptophan catabolism. Cell Death Differ 9(10):1069–1077. doi:10.1038/sj. cdd.4401073
Munn DH, Mellor AL (2013) Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol 34(3):137–143. doi:10.1016/j.it.2012.10.001
Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4(10):762–774. doi:10.1038/nri1457
Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M, Changsirivathanathamrong D, Wu BJ, Ball HJ, Thomas SR, Kapoor V, Celermajer DS, Mellor AL, Keaney JF Jr, Hunt NH, Stocker R (2010) Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 16(3):279–285. doi:10.1038/nm.2092
Zelante T, Fallarino F, Bistoni F, Puccetti P, Romani L (2009) Indoleamine 2,3-dioxygenase in infection: the paradox of an evasive strategy that benefits the host. Microbes Infect 11(1):133–141. doi:10.1016/j.micinf.2008.10.007
Blumenthal A, Nagalingam G, Huch JH, Walker L, Guillemin GJ, Smythe GA, Ehrt S, Britton WJ, Saunders BM (2012) M. tuberculosis induces potent activation of IDO-1, but this is not essential for the immunological control of infection. PLoS One 7(5):e37314. doi:10.1371/journal.pone.0037314
Mehra S, Pahar B, Dutta NK, Conerly CN, Philippi-Falkenstein K, Alvarez X, Kaushal D (2010) Transcriptional reprogramming in nonhuman primate (rhesus macaque) tuberculosis granulomas. PLoS One 5(8):e12266. doi:10.1371/journal.pone.0012266
Suzuki Y, Miwa S, Akamatsu T, Suzuki M, Fujie M, Nakamura Y, Inui N, Hayakawa H, Chida K, Suda T (2013) Indoleamine 2pleurisy. Int JTuberc Lung Dis 17(11):1501–1506. doi:10.5588/ijtld.13.0082
Suzuki Y, Suda T, Asada K, Miwa S, Suzuki M, Fujie M, Furuhashi K, Nakamura Y, Inui N, Shirai T, Hayakawa H, Nakamura H, Chida K (2012) Serum indoleamine 2,3-dioxygenase activity predicts prognosis of pulmonary tuberculosis. Clin Vaccine Immunol 19(3):436–442. doi:10.1128/CVI.05402-11
Mehra S, Alvarez X, Didier PJ, Doyle LA, Blanchard JL, Lackner AA, Kaushal D (2013) Granuloma correlates of protection against tuberculosis and mechanisms of immune modulation by Mycobacterium tuberculosis. J Infect Dis 207(7):1115–1127. doi:10.1093/infdis/jis778
Desvignes L, Ernst JD (2009) Interferon-gamma-responsive nonhematopoietic cells regulate the immune response to Mycobacterium tuberculosis. Immunity 31(6):974–985. doi:10.1016/j.immuni.2009.10.007
Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, Marshall B, Chandler P, Antonia SJ, Burgess R, Slingluff CL Jr, Mellor AL (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297(5588):1867–1870. doi:10.1126/science.1073514
Terness P, Bauer TM, Rose L, Dufter C, Watzlik A, Simon H, Opelz G (2002) Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196(4):447–457
Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Fioretti MC, Puccetti P (2006) Tryptophan catabolism generates autoimmune-preventive regulatory T cells. Transpl Immunol 17(1):58–60. doi:10.1016/j.trim.2006.09.017
Li Q, Li L, Liu Y, Fu X, Qiao D, Wang H, Lao S, Huang F, Wu C (2011) Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immuno-suppressive factors. Cell Mol Immunol 8(2):172–180. doi:10.1038/cmi.2010.80
Popov A, Abdullah Z, Wickenhauser C, Saric T, Driesen J, Hanisch FG, Domann E, Raven EL, Dehus O, Hermann C, Eggle D, Debey S, Chakraborty T, Kronke M, Utermohlen O, Schultze JL (2006) Indoleamine 2,3-dioxygenase-expressing dendritic cells form suppurative granulomas following Listeriamonocytogenes infection. J Clin Invest 116(12):3160–3170. doi:10.1172/JCI28996
Schmidt SK, Siepmann S, Kuhlmann K, Meyer HE, Metzger S, Pudelko S, Leineweber M, Daubener W (2012) Influence of tryp- tophan contained in 1-methyl-tryptophan on antimicrobial and immunoregulatory functions of indoleamine 2,3-dioxygenase. PLoS One 7(9):e44797. doi:10.1371/journal.pone.0044797
Ball HJ, Sanchez-Perez A, Weiser S, Austin CJ, Astelbauer F, Miu J, McQuillan JA, Stocker R, Jermiin LS, Hunt NH (2007) Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene 396(1):203–213. doi:10.1016/j. gene.2007.04.010
Divanovic S, Sawtell NM, Trompette A, Warning JI, Dias A, Cooper AM, Yap GS, Arditi M, Shimada K, Duhadaway JB, Prendergast GC, Basaraba RJ, Mellor AL, Munn DH, Aliberti J, Karp CL (2012) Opposing biological functions of tryptophan ca-tabolizing enzymes during intracellular infection. J Infect Dis 205(1):152–161. doi:10.1093/infdis/jir621
Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC (2007) Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res 67(15):7082–7087. doi:10.1158/0008-5472.CAN-07-1872
Metz R, Smith C, DuHadaway JB, Chandler P, Baban B, Merlo LM, Pigott E, Keough MP, Rust S, Mellor AL, Mandik-Nayak L, Muller AJ, Prendergast GC (2014) IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. Int Immunol 26(7):357–367. doi:10.1093/intimm/dxt073
Zhang YJ, Reddy MC, Ioerger TR, Rothchild AC, Dartois V, Schuster BM, Trauner A, Wallis D, Galaviz S, Huttenhower C, Sacchettini JC, Behar SM, Rubin EJ (2013) Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Cell 155(6):1296–1308. doi:10.1016/j.cell.2013.10.045
Deffert C, Cachat J, Krause KH (2014) Phagocyte NADPH oxidase, chronic granulomatous disease and mycobacterial infections. Cell Microbiol 16(8):1168–1178. doi:10.1111/cmi.12322
Yang CT, Cambier CJ, Davis JM, Hall CJ, Crosier PS, Ramakrishnan L (2012) Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages. Cell Host Microbe 12(3):301–312. doi:10.1016/j.chom.2012.07.009
Palanisamy GS, Kirk NM, Ackart DF, Shanley CA, Orme IM, Basaraba RJ (2011) Evidence for oxidative stress and defective antioxidant response in guinea pigs with tuberculosis. PLoS One 6(10):e26254. doi:10.1371/journal.pone.0026254
Deffert C, Schappi MG, Pache JC, Cachat J, Vesin D, Bisig R, Ma Mulone X, Kelkka T, Holmdahl R, Garcia I, Olleros ML, Krause KH (2014) Bacillus calmette-guerin infection in NADPH oxidase deficiency: defective mycobacterial sequestration and granuloma formation. PLoS Pathog 10(9):e1004325. doi:10.1371/journal.ppat.1004325
Bustamante J, Arias AA, Vogt G, Picard C, Galicia LB, Prando C, Grant AV, Marchal CC, Hubeau M, Chapgier A, de Beaucoudrey L, Puel A, Feinberg J, Valinetz E, Janniere L, Besse C, Boland A, Brisseau JM, Blanche S, Lortholary O, Fieschi C, Emile JF, Boisson-Dupuis S, Al-Muhsen S, Woda B, Newburger PE, Condino-Neto A, Dinauer MC, Abel L, Casanova JL (2011) Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobac-terial disease. Nat Immunol 12(3):213–221. doi:10.1038/ni.1992
Davis SL, Nuermberger EL, Um PK, Vidal C, Jedynak B, Pomper MG, Bishai WR, Jain SK (2009) Noninvasive pulmonary [18F]-2-fluoro-deoxy-D-glucose positron emission tomography correlates with bactericidal activity of tuberculosis drug treatment. Antimicrob Agents Chemother 53(11):4879–4884. doi:10.1128/ AAC.00789-09
Kim IJ, Lee JS, Kim SJ, Kim YK, Jeong YJ, Jun S, Nam HY, Kim JS (2008) Double-phase 18F-FDG PET-CT for determination of pulmonary tuberculoma activity. Eur J Nucl Med Mol Imaging 35(4):808–814. doi:10.1007/s00259-007-0585-0
Coleman MT, Maiello P, Tomko J, Frye LJ, Fillmore D, Janssen C, Klein E, Lin PL (2014) Early changes by (18)fluorodeoxyglucose positron emission tomography coregistered with computed to-mography predict outcome after Mycobacterium tuberculosis infection in cynomolgus macaques. Infect Immun 82(6):2400–2404. doi:10.1128/IAI.01599-13
Via LE, Schimel D, Weiner DM, Dartois V, Dayao E, Cai Y, Yoon YS, Dreher MR, Kastenmayer RJ, Laymon CM, Carny JE, Flynn JL, Herscovitch P, Barry CE 3rd (2012) Infection dynamics and response to chemotherapy in a rabbit model of tuberculosis using [(1)(8)F]2-fluoro-deoxy-D-glucose positron emission tomography and computed tomography. Antimicrob Agents Chemother 56(8):4391–4402. doi:10.1128/AAC.00531-12
Somashekar BS, Amin AG, Rithner CD, Troudt J, Basaraba R, Izzo A, Crick DC, Chatterjee D (2011) Metabolic profiling of lung granuloma in Mycobacterium tuberculosis infected guinea pigs: ex vivo 1H magic angle spinning NMR studies. J Proteome Res 10(9):4186–4195. doi:10.1021/pr2003352
Palsson-McDermott EM, O’Neill LA (2013) The Warburg effect then and now: from cancer to inflammatory diseases. Bioessays 35(11):965–973. doi:10.1002/bies.201300084
Shin JH, Yang JY, Jeon BY, Yoon YJ, Cho SN, Kang YH, Ryu do H, Hwang GS (2011) (1)H NMR-based metabolomic profiling in mice infected with Mycobacterium tuberculosis. J Proteome Res 10(5):2238–2247. doi:10.1021/pr101054m
Chen Y, Wu J, Tu L, Xiong X, Hu X, Huang J, Xu Z, Zhang X, Hu C, Hu X, Guo A, Wang Y, Chen H (2013) (1)H-NMR spectroscopy revealed Mycobacterium tuberculosis caused abnormal serum metabolic profile of cattle. PLoS One 8(9):e74507. doi:10.1371/journal.pone.0074507
Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513(7519):559–563. doi:10.1038/nature13490
Albina JE, Henry WL Jr, Mastrofrancesco B, Martin BA, Reichner JS (1995) Macrophage activation by culture in an anoxic environment. J Immunol 155(9):4391–4396
Jin Y, Calvert TJ, Chen B, Chicoine LG, Joshi M, Bauer JA, Liu Y, Nelin LD (2010) Mice deficient in Mkp-1 develop more severe pulmonary hypertension and greater lung protein levels of arginase in response to chronic hypoxia. Am J Physiol Heart Circ Physiol 298(5):H1518–1528. doi:10.1152/ajpheart.00813.2009
Vergadi E, Chang MS, Lee C, Liang OD, Liu X, Fernandez-Gonzalez A, Mitsialis SA, Kourembanas S (2011) Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. Circulation 123(18):1986–1995. doi:10.1161/ CIRCULATIONAHA.110.978627
Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O’Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153(6):1239–1251. doi:10.1016/j. cell .2013.05
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).
Author information
Authors and Affiliations
Corresponding authors
Additional information
This article is a contribution to the Special Issue on Immunopathology of Mycobacterial Diseases - Guest Editor: Stefan Kaufmann
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-015-0534-0