Journal Mobile Options
Table of Contents
Vol. 3, No. 5, 2011
Issue release date: August 2011
Section title: Research Article
Open Access Gateway
J Innate Immun 2011;3:508–518

Importance of Phagosomal Functionality for Growth Restriction of Mycobacterium tuberculosis in Primary Human Macrophages

Welin A.a · Raffetseder J.a · Eklund D.a · Stendahl O.a · Lerm M.a, b
aMedical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, and bCenter for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
email Corresponding Author

Dr. Amanda Welin

Medical Microbiology, Floor 12 Lab1

Department of Clinical and Experimental Medicine, Linköping University

SE–58185 Linköping (Sweden)

Tel. +46 10103 2059, E-Mail


  1. Scherr N, Jayachandran R, Mueller P, Pieters J: Interference of Mycobacterium tuberculosis with macrophage responses. Indian J Exp Biol 2009;47:401–406.
  2. Armstrong JA, Hart PD: Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J Exp Med 1971;134:713–740.
  3. Clemens DL, Horwitz MA: Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited. J Exp Med 1995;181:257–270.
  4. Russell DG: Mycobacterium tuberculosis: here today, and here tomorrow. Nat Rev Mol Cell Biol 2001;2:569–577.
  5. Via LE, Deretic D, Ulmer RJ, Hibler NS, Huber LA, Deretic V: Arrest of mycobacterial phagosome maturation is caused by a block in vesicle fusion between stages controlled by rab5 and rab7. J Biol Chem 1997;272:13326–13331.
  6. van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M, Peters PJ: M. Tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 2007;129:1287–1298.
  7. Meena LS, Rajni: Survival mechanisms of pathogenic Mycobacterium tuberculosis H37Rv. Febs J 2010;277:2416–2427.
  8. Rohde K, Yates RM, Purdy GE, Russell DG: Mycobacterium tuberculosis and the environment within the phagosome. Immunol Rev 2007;219:37–54.
  9. Sturgill-Koszycki S, Schlesinger PH, Chakraborty P, Haddix PL, Collins HL, Fok AK, Allen RD, Gluck SL, Heuser J, Russell DG: Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-atpase. Science 1994;263:678–681.
  10. Stewart GR, Patel J, Robertson BD, Rae A, Young DB: Mycobacterial mutants with defective control of phagosomal acidification. PLoS Pathog 2005;1:269–278.
  11. Schaible UE, Sturgill-Koszycki S, Schlesinger PH, Russell DG: Cytokine activation leads to acidification and increases maturation of Mycobacterium avium-containing phagosomes in murine macrophages. J Immunol 1998;160:1290–1296.
  12. Vergne I, Chua J, Singh SB, Deretic V: Cell biology of Mycobacterium tuberculosis phagosome. Annu Rev Cell Dev Biol 2004;20:367–394.
  13. Pethe K, Swenson DL, Alonso S, Anderson J, Wang C, Russell DG: Isolation of Mycobacterium tuberculosis mutants defective in the arrest of phagosome maturation. Proc Natl Acad Sci USA 2004;101:13642–13647.
  14. Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Bolcskei PL, Wagner M, Akira S, Norgard MV, Belisle JT, Godowski PJ, Bloom BR, Modlin RL: Induction of direct antimicrobial activity through mammalian Toll-like receptors. Science 2001;291:1544–1547.
  15. Reljic R, Stylianou E, Balu S, Ma JK: Cytokine interactions that determine the outcome of mycobacterial infection of macrophages. Cytokine 2010;51:42–46.
  16. Valdivia RH, Hromockyj AE, Monack D, Ramakrishnan L, Falkow S: Applications for green fluorescent protein (GFP) in the study of host-pathogen interactions. Gene 1996;173:47–52.
  17. Welin A, Winberg ME, Abdalla H, Sarndahl E, Rasmusson B, Stendahl O, Lerm M: Incorporation of Mycobacterium tuberculosis lipoarabinomannan into macrophage membrane rafts is a prerequisite for the phagosomal maturation block. Infect Immun 2008;76:2882–2887.
  18. Eklund D, Welin A, Schon T, Stendahl O, Huygen K, Lerm M: Validation of a medium-throughput method for evaluation of intracellular growth of Mycobacterium tuberculosis. Clin Vaccine Immunol 2010;17:513–517.
  19. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM: Macrophages that have ingested apoptotic cells in vitro inhibit pro-inflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J Clin Invest 1998;101:890–898.
  20. Savill JS, Wyllie AH, Henson JE, Walport MJ, Henson PM, Haslett C: Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J Clin Invest 1989;83:865–875.
  21. Lee BY, Clemens DL, Horwitz MA: The metabolic activity of Mycobacterium tuberculosis, assessed by use of a novel inducible GFP expression system, correlates with its capacity to inhibit phagosomal maturation and acidification in human macrophages. Mol Microbiol 2008;68:1047–1060.
  22. Lee JS, Krause R, Schreiber J, Mollenkopf HJ, Kowall J, Stein R, Jeon BY, Kwak JY, Song MK, Patron JP, Jorg S, Roh K, Cho SN, Kaufmann SH: Mutation in the transcriptional regulator PHOP contributes to avirulence of Mycobacterium tuberculosis H37Ra strain. Cell Host Microbe 2008;3:97–103.
  23. Sturgill-Koszycki S, Schaible UE, Russell DG: Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis. EMBO J 1996;15:6960–6968.
  24. Ullrich HJ, Beatty WL, Russell DG: Direct delivery of procathepsin d to phagosomes: implications for phagosome biogenesis and parasitism by Mycobacterium. Eur J Cell Biol 1999;78:739–748.
  25. Rathman M, Sjaastad MD, Falkow S: Acidification of phagosomes containing Salmonella typhimurium in murine macrophages. Infect Immun 1996;64:2765–2773.
  26. Kusner DJ: Mechanisms of mycobacterial persistence in tuberculosis. Clin Immunol 2005;114:239–247.
  27. de Chastellier C: The many niches and strategies used by pathogenic mycobacteria for survival within host macrophages. Immunobiology 2009;214:526–542.
  28. Malik ZA, Thompson CR, Hashimi S, Porter B, Iyer SS, Kusner DJ: Cutting edge: Mycobacterium tuberculosis blocks Ca2+ signaling and phagosome maturation in human macrophages via specific inhibition of sphingosine kinase. J Immunol 2003;170:2811–2815.
  29. Fratti RA, Chua J, Deretic V: Induction of p38 mitogen-activated protein kinase reduces early endosome autoantigen 1 (EEA1) recruitment to phagosomal membranes. J Biol Chem 2003;278:46961–46967.
  30. O’Leary S, O’Sullivan MP, Keane J: IL-10 blocks phagosome maturation in Mycobacterium tuberculosis-infected human macrophages. Am J Respir Cell Mol Biol DOI: 10.1165/rcmb.2010-0319OC [Epub ahead of print].

    External Resources

  31. Harris J, Hope JC, Keane J: Tumor necrosis factor blockers influence macrophage responses to Mycobacterium tuberculosis. J Infect Dis 2008;198:1842–1850.
  32. Gomes MS, Paul S, Moreira AL, Appelberg R, Rabinovitch M, Kaplan G: Survival of Mycobacterium avium and Mycobacterium tuberculosis in acidified vacuoles of murine macrophages. Infect Immun 1999;67:3199–3206.
  33. Deretic V: Autophagy, an immunologic magic bullet: Mycobacterium tuberculosis phagosome maturation block and how to bypass it. Future Microbiol 2008;3:517–524.
  34. Flannagan RS, Cosio G, Grinstein S: Antimicrobial mechanisms of phagocytes and bacterial evasion strategies. Nat Rev Microbiol 2009;7:355–366.
  35. Jordao L, Bleck CK, Mayorga L, Griffiths G, Anes E: On the killing of mycobacteria by macrophages. Cell Microbiol 2008;10:529–548.
  36. Vandal OH, Pierini LM, Schnappinger D, Nathan CF, Ehrt S: A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis. Nat Med 2008;14:849–854.
  37. Huynh KK, Grinstein S: Regulation of vacuolar pH and its modulation by some microbial species. Microbiol Mol Biol Rev 2007;71:452–462.
  38. Fratti RA, Chua J, Vergne I, Deretic V: Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc Natl Acad Sci USA 2003;100:5437–5442.
  39. Kinchen JM, Ravichandran KS: Phagosome maturation: going through the acid test. Nat Rev Mol Cell Biol 2008;9:781–795.
  40. Sun-Wada GH, Tabata H, Kawamura N, Aoyama M, Wada Y: Direct recruitment of H+-ATPase from lysosomes for phagosomal acidification. J Cell Sci 2009;122:2504–2513.