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A bug’s life in the granuloma

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Abstract

The granuloma is the defining feature of the host response to infection with Mycobacterium tuberculosis (Mtb). Despite knowing of its existence for centuries, much remains unclear regarding the host and bacterial factors that contribute to granuloma formation, heterogeneity of presentation, and the forces at play within. Mtb is highly adapted to life within the granuloma and employs many unique strategies to both create a niche within the host as well as survive the stresses imposed upon it. Adding to the complexity of the granuloma is the vast range of pathology observed, often within the same individual. Here, we explore some of the many ways in which Mtb crafts the immune response to its liking and builds a variety of granuloma features that contribute to its survival. We also consider the multitude of ways that Mtb is adapted to life in the granuloma and how variability in the deployment of these strategies may result in different fates for both the bacterium and the host. It is through better understanding of these complex interactions that we may begin to strategize novel approaches for tuberculosis treatments.

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References

  1. Nunes-Alves C et al (2014) In search of a new paradigm for protective immunity to TB. Nat Rev Microbiol 12(4):289–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Achkar JM, Chan J, Casadevall A (2015) B cells and antibodies in the defense against Mycobacterium tuberculosis infection. Immunol Rev 264(1):167–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gold MC et al (2010) Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol 8(6), e1000407

    Article  PubMed  PubMed Central  Google Scholar 

  4. Van Rhijn I et al (2013) A conserved human T cell population targets mycobacterial antigens presented by CD1b. Nat Immunol 14(7):706–713

    Article  PubMed  PubMed Central  Google Scholar 

  5. Havlir DV et al (1991) Selective expansion of human gamma delta T cells by monocytes infected with live Mycobacterium tuberculosis. J Clin Invest 87(2):729–733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Canetti G (1968) Biology of the mycobacterioses. Pathogenesis of tuberculosis in man. Ann N Y Acad Sci 154(1):13–18

    Article  CAS  PubMed  Google Scholar 

  7. Lin PL et al (2009) Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model. Infect Immun 77(10):4631–4642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lin PL et al (2014) Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med 20(1):75–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gideon HP et al (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

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hussell T, Bell TJ (2014) Alveolar macrophages: plasticity in a tissue-specific context. Nat Rev Immunol 14(2):81–93

    Article  CAS  PubMed  Google Scholar 

  12. Mattila JT et al (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Marino S et al (2015) Macrophage polarization drives granuloma outcome during Mycobacterium tuberculosis infection. Infect Immun 83(1):324–338

    Article  PubMed  PubMed Central  Google Scholar 

  14. Peyron P et al (2008) Foamy macrophages from tuberculous patients’ granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog 4(11):e1000204

    Article  PubMed  PubMed Central  Google Scholar 

  15. Rhoades ER et al (2005) Cell wall lipids from Mycobacterium bovis BCG are inflammatory when inoculated within a gel matrix: characterization of a new model of the granulomatous response to mycobacterial components. Tuberculosis (Edinb) 85(3):159–176

    Article  CAS  Google Scholar 

  16. Kim MJ et al (2010) Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism. EMBO Mol Med 2(7):258–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dkhar HK et al (2014) Mycobacterium tuberculosis keto-mycolic acid and macrophage nuclear receptor TR4 modulate foamy biogenesis in granulomas: a case of a heterologous and noncanonical ligand-receptor pair. J Immunol 193(1):295–305

    Article  CAS  PubMed  Google Scholar 

  18. Puissegur MP et al (2007) Mycobacterial lipomannan induces granuloma macrophage fusion via a TLR2-dependent, ADAM9- and beta1 integrin-mediated pathway. J Immunol 178(5):3161–3169

    Article  CAS  PubMed  Google Scholar 

  19. Beatty WL, Ullrich HJ, Russell DG (2001) Mycobacterial surface moieties are released from infected macrophages by a constitutive exocytic event. Eur J Cell Biol 80(1):31–40

    Article  CAS  PubMed  Google Scholar 

  20. Geisel RE et al (2005) In vivo activity of released cell wall lipids of Mycobacterium bovis bacillus Calmette-Guérin is due principally to trehalose mycolates. J Immunol 174(8):5007–5015

    Article  CAS  PubMed  Google Scholar 

  21. Bhatnagar S et al (2007) Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood 110(9):3234–3244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Singh PP et al (2011) Exosomes released from M. tuberculosis infected cells can suppress IFN-γ mediated activation of naïve macrophages. PLoS One 6(4):e18564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rath P et al (2013) Genetic regulation of vesiculogenesis and immunomodulation in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 110(49):E4790–E4797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Elkington P et al (2011) MMP-1 drives immunopathology in human tuberculosis and transgenic mice. J Clin Invest 121(5):1827–1833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Al Shammari B et al (2015) The extracellular matrix regulates granuloma necrosis in tuberculosis. J Infect Dis 212(3):463–473

    Article  PubMed  Google Scholar 

  26. Volkman HE et al (2010) Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 327(5964):466–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Via LE et al (2008) Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates. Infect Immun 76(6):2333–2340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Leistikow RL et al (2010) The Mycobacterium tuberculosis DosR regulon assists in metabolic homeostasis and enables rapid recovery from nonrespiring dormancy. J Bacteriol 192(6):1662–1670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Boon C, Dick T (2002) Mycobacterium bovis BCG response regulator essential for hypoxic dormancy. J Bacteriol 184(24):6760–6767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sherman DR et al (2001) Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha-crystallin. Proc Natl Acad Sci U S A 98(13):7534–7539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wayne LG, Hayes LG (1996) An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect Immun 64(6):2062–2069

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Oehlers SH et al (2015) Interception of host angiogenic signalling limits mycobacterial growth. Nature 517(7536):612–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Datta M et al (2015) Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery. Proc Natl Acad Sci U S A 112(6):1827–1832

  34. Cunningham-Bussel A, Zhang T, Nathan CF (2013) Nitrite produced by Mycobacterium tuberculosis in human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression. Proc Natl Acad Sci U S A 110(45):E4256–E4265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Firmani MA, Riley LW (2002) Reactive nitrogen intermediates have a bacteriostatic effect on Mycobacterium tuberculosis in vitro. J Clin Microbiol 40(9):3162–3166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chan J et al (1995) Effects of nitric oxide synthase inhibitors on murine infection with Mycobacterium tuberculosis. Infect Immun 63(2):736–740

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kumar A et al (2007) Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor. Proc Natl Acad Sci U S A 104(28):11568–11573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Braunstein M et al (2003) SecA2 functions in the secretion of superoxide dismutase A and in the virulence of Mycobacterium tuberculosis. Mol Microbiol 48(2):453–464

    Article  CAS  PubMed  Google Scholar 

  39. Nambi S et al (2015) The oxidative stress network of Mycobacterium tuberculosis reveals coordination between radical detoxification systems. Cell Host Microbe 17(6):829–837

    Article  CAS  PubMed  Google Scholar 

  40. Hood MI, Skaar EP (2012) Nutritional immunity: transition metals at the pathogen-host interface. Nat Rev Microbiol 10(8):525–537

    Article  CAS  PubMed  Google Scholar 

  41. Niederweis M (2008) Nutrient acquisition by mycobacteria. Microbiology 154(Pt 3):679–692

    Article  CAS  PubMed  Google Scholar 

  42. Botella H et al (2011) Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages. Cell Host Microbe 10(3):248–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rowland JL, Niederweis M (2012) Resistance mechanisms of Mycobacterium tuberculosis against phagosomal copper overload. Tuberculosis (Edinb) 92(3):202–210

    Article  CAS  Google Scholar 

  44. Van der Geize R et al (2007) A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages. Proc Natl Acad Sci U S A 104(6):1947–1952

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pandey AK, Sassetti CM (2008) Mycobacterial persistence requires the utilization of host cholesterol. Proc Natl Acad Sci U S A 105(11):4376–4380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ehrt S, Rhee K (2013) Mycobacterium tuberculosis metabolism and host interaction: mysteries and paradoxes. Curr Top Microbiol Immunol 374:163–188

    CAS  PubMed  Google Scholar 

  47. Schnappinger D et al (2003) Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: insights into the phagosomal environment. J Exp Med 198(5):693–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. McKinney JD, zu Bentrup KH, Muñoz-Elías EJ (2000) Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406:735

    Article  CAS  PubMed  Google Scholar 

  49. Muñoz-Elías EJ, McKinney JD (2005) Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat Med 11(6):638–644

    Article  PubMed  PubMed Central  Google Scholar 

  50. Zhang YJ et al (2013) Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Cell 155(6):1296–1308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Eoh H, Rhee KY (2014) Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids. Proc Natl Acad Sci U S A 111(13):4976–4981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee W et al (2013) Intracellular Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic stress. J Biol Chem 288(10):6788–6800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Singh A et al (2009) Mycobacterium tuberculosis WhiB3 maintains redox homeostasis by regulating virulence lipid anabolism to modulate macrophage response. PLoS Pathog 5(8), e1000545

    Article  PubMed  PubMed Central  Google Scholar 

  54. Prideaux B et al (2015) The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med

  55. Talaat AM et al (2004) The temporal expression profile of Mycobacterium tuberculosis infection in mice. Proc Natl Acad Sci U S A 101(13):4602–4607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wilkinson RJ et al (2001) An increase in expression of a Mycobacterium tuberculosis mycolyl transferase gene (fbpB) occurs early after infection of human monocytes. Mol Microbiol 39(3):813–821

    Article  CAS  PubMed  Google Scholar 

  57. Manina G, Dhar N, McKinney JD (2015) Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. Cell Host Microbe 17(1):32–46

    Article  CAS  PubMed  Google Scholar 

  58. Sánchez-Romero MAA, Cota I, Casadesús J (2015) DNA methylation in bacteria: from the methyl group to the methylome. Curr Opin Microbiol 25:9–16

    Article  PubMed  Google Scholar 

  59. Casadesús J, Low DA (2013) Programmed heterogeneity: epigenetic mechanisms in bacteria. J Biol Chem 288(20):13929–13935

    Article  PubMed  PubMed Central  Google Scholar 

  60. Shell SS et al (2013) DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis. PLoS Pathog 9(7):e1003419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Primm TP et al (2000) The stringent response of Mycobacterium tuberculosis is required for long-term survival. J Bacteriol 182(17):4889–4898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sureka K et al (2008) Positive feedback and noise activate the stringent response regulator rel in mycobacteria. PLoS One 3:e1771

    Article  PubMed  PubMed Central  Google Scholar 

  63. Veening J-WW, Smits WK, Kuipers OP (2008) Bistability, epigenetics, and bet-hedging in bacteria. Annu Rev Microbiol 62:193–210

    Article  CAS  PubMed  Google Scholar 

  64. Tiwari A et al (2010) The interplay of multiple feedback loops with post-translational kinetics results in bistability of mycobacterial stress response. Phys Biol 7(3):036005

    Article  PubMed  PubMed Central  Google Scholar 

  65. Aldridge BB et al (2012) Asymmetry and aging of mycobacterial cells lead to variable growth and antibiotic susceptibility. Science (New York, NY) 335(6064):100–104

    Article  CAS  Google Scholar 

  66. Comas I et al (2013) Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet 45(10):1176–1182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Constance J. Martin, Allison F. Carey & Sarah M. Fortune

  2. Ragon Institute of Massachusetts General Hospital, Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA

    Constance J. Martin & Sarah M. Fortune

  3. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Allison F. Carey

Authors
  1. Constance J. Martin
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  2. Allison F. Carey
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  3. Sarah M. Fortune
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Corresponding author

Correspondence to Sarah M. Fortune.

Additional information

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

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Martin, C.J., Carey, A.F. & Fortune, S.M. A bug’s life in the granuloma. Semin Immunopathol 38, 213–220 (2016). https://doi.org/10.1007/s00281-015-0533-1

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