Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Interplay between mycobacteria and host signalling pathways

Nature Reviews Microbiology volume 2, pages 189–202 (2004)Cite this article

Key Points

  • Although tuberculosis (TB) kills about two million people each year, no new drug for its treatment has been introduced in the past 30 years. Knowledge of the mechanisms by which mycobacteria are able to circumvent host defence responses is essential to the quest for the development of new drug candidates for the treatment of TB.

  • Pathogenic mycobacteria use several mechanisms that allow them to survive in the hostile environment of the host cell. These include preventing phagosomal maturation, modifying the host apoptotic response and blocking host-signalling pathways that would otherwise trigger an antibacterial response.

  • Mycobacteria block phagosomal maturation through lipid molecules, such as Man-LAM, that inhibit signalling through Ca2+/calmodulin and phosphatidylinositol-3-kinase pathways. However, the details of the mechanisms that mycobacteria use to suppress these pathways are not well understood.

  • The suppression of host-cell apoptosis by pathogenic bacteria early in infection facilitates their proliferation and survival. This inhibition of apoptosis takes place through several mechanisms, including preventing increases in the Ca2+ concentration that trigger cytochrome c release from mitochondria, blocking the function of the pro-apoptotic protein Bad and inhibiting TNF-α production.

  • Pathogenic mycobacteria suppress the MAPK and JAK/STAT signalling pathways that are crucial for many innate and adaptive immune responses to infection. They suppress the sustained activation of the MAPKs p38 and ERK1/2 and are able to inhibit JAK/STAT signalling by inhibiting phosphorylation of JAKs and translocation of STAT to the nucleus, and by inducing the expression of the SOCS protein, which binds and inactivates JAKs.

  • The prevention of dendritic cell maturation and the activation of T cells by pathogenic bacteria is another method by which they minimize the host immune response. Binding of Man-LAM to DC-SIGN receptors on dendritic cells prevents their maturation and leads to the secretion of IL-10, an immunosuppressive chemokine.

  • The release of the complete genome sequence of Mycobacterium tuberculosis has identified eukaryotic-like protein kinases and phosphatases. In several bacterial species, protein kinases and phosphatases are important virulence mediators that disrupt host-signalling networks. Some of the mycobacterial kinases and phosphatases might modulate the eukaryotic signalling machinery for intracellular survival.

  • Mycobacterial kinases and phosphatases show potential as targets for TB therapeutics; kinase inhibitors suppress mycobacterial infection in vitro; inhibitors of both kinases and phosphatases have been developed for the treatment of other diseases. As our understanding of the mechanisms involved in mycobacterial survival increases, the range of other potential targets for anti-TB drugs will expand.

Abstract

Pathogenesis by mycobacteria requires the exploitation of host-cell signalling pathways to enhance the intracellular survival and persistence of the pathogen. The disruption of these pathways by mycobacteria causes impaired maturation of phagosomes into phagolysosomes, modulates host-cell apoptotic pathways and suppresses the host immune response. This review highlights the strategies employed by mycobacteria to subvert host-cell signalling and identifies key molecules involved in these processes that might serve as potential targets for new antimycobacterial therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of the differential regulation of host-cell signalling by pathogenic and non-pathogenic mycobacteria.
Figure 2: Pathogenic mycobacteria block the phagosomal maturation pathway.
Figure 3: Comparison of phagosomes harbouring pathogenic or non-pathogenic mycobacteria.
Figure 4: Inhibition of host apoptotic pathways by pathogenic mycobacteria.
Figure 5: Disruption of macrophage signalling pathways by mycobacteria.
Figure 6: Disruption of dendritic-cell signalling pathways by mycobacteria.

Similar content being viewed by others

References

  1. Butler, D. New fronts in an old war. Nature 406, 670–672 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Rosenberger, C. M. & Finlay, B. B. Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens. Nature Rev. Mol. Cell Biol. 4, 385–396 (2003).

    Article  CAS  Google Scholar 

  3. Beatty, W. L. et al. Trafficking and release of mycobacterial lipids from infected macrophages. Traffic 1, 235–247 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Brennan, P. J. & Nikaido, H. The envelope of mycobacteria. Annu. Rev. Biochem. 64, 29–63 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Ernst, J. D. Macrophage receptors for Mycobacterium tuberculosis. Infect. Immun. 66, 1277–1281 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Schlesinger, L. S., Bellinger-Kawahara, C. G., Payne, N. R. & Horwitz, M. A. Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J. Immunol. 144, 2771–2780 (1990).

    CAS  PubMed  Google Scholar 

  7. Caron, E. & Hall, A. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282, 1717–1721 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Hellwig, S. M. et al. Targeting to Fcγ receptors, but not CR3 (CD11b/CD18), increases clearance of Bordetella pertussis. J. Infect. Dis. 183, 871–879 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Melo, M. D., Catchpole, I. R., Haggar, G. & Stokes, R. W. Utilization of CD11b knockout mice to characterize the role of complement receptor 3 (CR3, CD11b/CD18) in the growth of Mycobacterium tuberculosis in macrophages. Cell Immunol. 205, 13–23 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Vieira, O. V., Botelho, R. J. & Grinstein, S. Phagosome maturation: aging gracefully. Biochem. J. 366, 689–704 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Clemens, D. L. & Horwitz, M. A. Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited. J. Exp. Med. 181, 257–270 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Sturgill-Koszycki, S. et al. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 263, 678–681 (1994). This paper showed for the first time that mycobacterial phagosomes do not recruit the ATP-dependent H+ pumps that bring about acidification to their membranes.

    Article  CAS  PubMed  Google Scholar 

  13. Armstrong, J. A. & Hart, P. D. Phagosome–lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual nonfusion pattern and observations on bacterial survival. J. Exp. Med. 142, 1–16 (1975). This is the first report of the failure of phagosomes in cells infected with pathogenic mycobacteria to fuse with lysosomes.

    Article  CAS  PubMed  Google Scholar 

  14. Russell, D. G. Mycobacterium tuberculosis: here today, and here tomorrow. Nature Rev. Mol. Cell Biol. 2, 569–577 (2001).

    Article  CAS  Google Scholar 

  15. Ferrari, G., Langen, H., Naito, M. & Pieters, J. A coat protein on phagosomes involved in the intracellular survival of mycobacteria. Cell 97, 435–447 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Deretic, V. & Fratti, R. A. Mycobacterium tuberculosis phagosome. Mol. Microbiol. 31, 1603–1609 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Schuller, S., Neefjes, J., Ottenhoff, T., Thole, J. & Young, D. Coronin is involved in uptake of Mycobacterium bovis BCG in human macrophages but not in phagosome maintenance. Cell. Microbiol. 3, 785–793 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Via, L. E. et al. Arrest of mycobacterial phagosome maturation is caused by a block in vesicle fusion between stages controlled by Rab5 and Rab7. J. Biol. Chem. 272, 13326–13331 (1997). Together with reference 15, this paper describes the stable association of TACO and Rab5 with phagosomes containing mycobacteria.

    Article  CAS  PubMed  Google Scholar 

  19. Fratti, R. A., Backer, J. M., Gruenberg, J., Corvera, S. & Deretic, V. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J. Cell Biol. 154, 631–644 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Christoforidis, S. et al. Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nature Cell Biol. 1, 249–252 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Jaconi, M. E. et al. Cytosolic free calcium elevation mediates the phagosome–lysosome fusion during phagocytosis in human neutrophils. J. Cell Biol. 110, 1555–1564 (1990).

    Article  CAS  PubMed  Google Scholar 

  22. Wurmser, A. E., Gary, J. D. & Emr, S. D. Phosphoinositide-3-kinases and their FYVE domain-containing effectors as regulators of vacuolar/lysosomal membrane trafficking pathways. J. Biol. Chem. 274, 9129–9132 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Carafoli, E. Calcium signaling: a tale for all seasons. Proc. Natl Acad. Sci. USA 99, 1115–1122 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Malik, Z. A., Iyer, S. S. & Kusner, D. J. Mycobacterium tuberculosis phagosomes exhibit altered calmodulin-dependent signal transduction: contribution to inhibition of phagosome-lysosome fusion and intracellular survival in human macrophages. J. Immunol. 166, 3392–3401 (2001). This paper gives a clear demonstration of the role of Ca2+- and calmodulin-mediated signalling pathways in blocking the maturation of phagosomes bearing pathogenic mycobacteria.

    Article  CAS  PubMed  Google Scholar 

  25. Rich, R. C. & Schulman, H. Substrate-directed function of calmodulin in autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 273, 28424–28429 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Peters, C. & Mayer, A. Ca2+/calmodulin signals the completion of docking and triggers a late step of vacuole fusion. Nature 396, 575–580 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Malik, Z. A., Denning, G. M. & Kusner, D. J. Inhibition of Ca2+ signaling by Mycobacterium tuberculosis is associated with reduced phagosome–lysosome fusion and increased survival within human macrophages. J. Exp. Med. 191, 287–302 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rojas, M., Garcia, L. F., Nigou, J., Puzo, G. & Olivier, M. Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca2+-dependent cell signaling. J. Infect. Dis. 182, 240–251 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Malik, Z. A. et al. Cutting edge: Mycobacterium tuberculosis blocks Ca2+ signaling and phagosome maturation in human macrophages via specific inhibition of sphingosine kinase. J. Immunol. 170, 2811–2815 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Spiegel, S. & Milstien, S. Sphingosine 1-phosphate, a key cell signaling molecule. J. Biol. Chem. 277, 25851–25854 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Patki, V. et al. Identification of an early endosomal protein regulated by phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA 94, 7326–7330 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vergne, I., Chua, J. & Deretic, V. Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/calmodulin-PI3K hVPS34 cascade. J. Exp. Med. 198, 653–659 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fratti, R. A., Chua, J., Vergne, I. & Deretic, V. Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc. Natl Acad. Sci. USA 100, 5437–5442 (2003). References 32 and 33 describe the host cell signalling molecules that are involved in mycobacterial phagosome maturation and also define mycobacterial glycolipids, such as Man-LAM, as critical mycobacterial virulence factors that block phagolysosomal trafficking.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Anes, E. et al. Selected lipids activate phagosome actin assembly and maturation resulting in killing of pathogenic mycobacteria. Nature Cell Biol. 5, 793–802 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Taunton, J. Actin filament nucleation by endosomes, lysosomes and secretory vesicles. Curr. Opin. Cell Biol. 13, 85–91 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Spira, A. et al. Apoptosis genes in human alveolar macrophages infected with virulent or attenuated M. tuberculosis. Am. J. Respir. Cell Mol. Biol. 29 545–551 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Keane, J., Remold, H. G. & Kornfeld, H. Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. J. Immunol. 164, 2016–2020 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Nigou, J. et al. Mycobacterial lipoarabinomannans: modulators of dendritic cell function and the apoptotic response. Microbes Infect. 4, 945–953 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Szalai, G., Krishnamurthy, R. & Hajnoczky, G. Apoptosis driven by IP3-linked mitochondrial calcium signals. EMBO J. 18, 6349–6361 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maiti, D., Bhattacharyya, A. & Basu, J. Lipoarabinomannan from Mycobacterium tuberculosis promotes macrophage survival by phosphorylating Bad through a phosphatidylinositol 3-kinase/Akt pathway. J. Biol. Chem. 276, 329–333 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Esdar, C., Milasta, S., Maelicke, A. & Herget, T. Differentiation-associated apoptosis of neural stem cells is effected by Bcl-2 overexpression: impact on cell lineage determination. Eur. J. Cell Biol. 80, 539–553 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Brazil, D. P., Park, J. & Hemmings, B. A. PKB binding proteins. Getting in on the Akt. Cell 111, 293–303 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Balcewicz-Sablinska, M. K., Keane, J., Kornfeld, H. & Remold, H. G. Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-α. J. Immunol. 161, 2636–2641 (1998).

    CAS  PubMed  Google Scholar 

  44. Bhattacharyya, A. et al. Execution of macrophage apoptosis by Mycobacterium avium through apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase signaling and caspase 8 activation. J. Biol. Chem. 278, 26517–26525 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Kobayashi, S. D. et al. Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils. Proc. Natl Acad. Sci. USA 100, 10948–10953 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Johnson, G. L. & Lapadat, R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911–1912 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Roach, S. K. & Schorey, J. S. Differential regulation of the mitogen-activated protein kinases by pathogenic and nonpathogenic mycobacteria. Infect. Immun. 70, 3040–3052 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Blumenthal, A., Ehlers, S., Ernst, M., Flad, H. D. & Reiling, N. Control of mycobacterial replication in human macrophages: roles of extracellular signal-regulated kinases 1 and 2 and p38 mitogen-activated protein kinase pathways. Infect. Immun. 70, 4961–4967 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Reiling, N., Blumenthal, A., Flad, H. D., Ernst, M. & Ehlers, S. Mycobacteria-induced TNF-α and IL-10 formation by human macrophages is differentially regulated at the level of mitogen-activated protein kinase activity. J. Immunol. 167, 3339–3345 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Schorey, J. S. & Cooper, A. M. Macrophage signalling upon mycobacterial infection: the MAP kinases lead the way. Cell. Microbiol. 5, 133–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Orth, K. Function of the Yersinia effector YopJ. Curr. Opin. Microbiol. 5, 38–43 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Orth, K. et al. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285, 1920–1923 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Lin, S. L., Le, T. X. & Cowen, D. S. SptP, a Salmonella typhimurium type III-secreted protein, inhibits the mitogen-activated protein kinase pathway by inhibiting Raf activation. Cell. Microbiol. 5, 267–275 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Tse, H. M., Josephy, S. I., Chan, E. D., Fouts, D. & Cooper, A. M. Activation of the mitogen-activated protein kinase signaling pathway is instrumental in determining the ability of Mycobacterium avium to grow in murine macrophages. J. Immunol. 168, 825–833 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. van den, B. B. et al. p38 mitogen-activated protein kinase inhibition increases cytokine release by macrophages in vitro and during infection in vivo. J. Immunol. 166, 582–587 (2001).

    Article  Google Scholar 

  56. Godl, K. et al. An efficient proteomics method to identify the cellular targets of protein kinase inhibitors. Proc. Natl Acad. Sci. USA 100, 15434–15439 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Riedel, D. D. & Kaufmann, S. H. Chemokine secretion by human polymorphonuclear granulocytes after stimulation with Mycobacterium tuberculosis and lipoarabinomannan. Infect. Immun. 65, 4620–4623 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Perskvist, N., Zheng, L. & Stendahl, O. Activation of human neutrophils by Mycobacterium tuberculosis H37Ra involves phospholipase Cγ2, Shc adapter protein, and p38 mitogen-activated protein kinase. J. Immunol. 164, 959–965 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Mitsuyama, T., Takeshige, K. & Minakami, S. Tyrosine phosphorylation is involved in the respiratory burst of electropermeabilized human neutrophils at a step before diacylglycerol formation by phospholipase C. FEBS Lett. 322, 280–284 (1993).

    Article  CAS  PubMed  Google Scholar 

  60. Knutson, K. L., Hmama, Z., Herrera-Velit, P., Rochford, R. & Reiner, N. E. Lipoarabinomannan of Mycobacterium tuberculosis promotes protein tyrosine dephosphorylation and inhibition of mitogen-activated protein kinase in human mononuclear phagocytes. Role of the Src homology 2 containing tyrosine phosphatase 1. J. Biol. Chem. 273, 645–652 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Decker, T., Stockinger, S., Karaghiosoff, M., Muller, M. & Kovarik, P. IFNs and STATs in innate immunity to microorganisms. J. Clin. Invest 109, 1271–1277 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shtrichman, R. & Samuel, C. E. The role of γ-interferon in antimicrobial immunity. Curr. Opin. Microbiol. 4, 251–259 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. MacMicking, J. D., Taylor, G. A. & McKinney, J. D. Immune control of tuberculosis by IFN-γ-inducible LRG-47. Science 302, 654–659 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Hussain, S., Zwilling, B. S. & Lafuse, W. P. Mycobacterium avium infection of mouse macrophages inhibits IFN-γ Janus kinase–STAT signaling and gene induction by down-regulation of the IFN-γ receptor. J. Immunol. 163, 2041–2048 (1999).

    CAS  PubMed  Google Scholar 

  65. Ting, L. M., Kim, A. C., Cattamanchi, A. & Ernst, J. D. Mycobacterium tuberculosis inhibits IFN-γ transcriptional responses without inhibiting activation of STAT1. J. Immunol. 163, 3898–3906 (1999).

    CAS  PubMed  Google Scholar 

  66. Dupuis, S. et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293, 300–303 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Imai, K., Kurita-Ochiai, T. & Ochiai, K. Mycobacterium bovis bacillus Calmette–Guerin infection promotes SOCS induction and inhibits IFN-γ-stimulated JAK/STAT signaling in J774 macrophages. FEMS Immunol. Med. Microbiol. 39, 173–180 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Van Kooyk, Y. & Geijtenbeek, T. B. DC-SIGN: escape mechanism for pathogens. Nature Rev. Immunol. 3, 697–709 (2003).

    Article  CAS  Google Scholar 

  69. Tsuji, S. et al. Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette–Guerin: involvement of toll-like receptors. Infect. Immun. 68, 6883–6890 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Underhill, D. M., Ozinsky, A., Smith, K. D. & Aderem, A. Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc. Natl Acad. Sci. USA 96, 14459–14463 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lopez, M. et al. The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis through Toll-like receptor-2. J. Immunol. 170, 2409–2416 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Aliprantis, A. O. et al. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285, 736–739 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Geijtenbeek, T. B. et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197, 7–17 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tailleux, L. et al. DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J. Exp. Med. 197, 121–127 (2003). Together with reference 73, these authors describe how mycobacteria enter dendritic cells and that certain receptor pathways allow the pathogens to escape bactericidal killing by modulating TLR signalling pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nigou, J., Zelle-Rieser, C., Gilleron, M., Thurnher, M. & Puzo, G. Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. J. Immunol. 166, 7477–7485 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Redpath, S., Ghazal, P. & Gascoigne, N. R. Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol. 9, 86–92 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Engering, A., Geijtenbeek, T. B. & van Kooyk, Y. Immune escape through C-type lectins on dendritic cells. Trends Immunol. 23, 480–485 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Hamilton, V. T., Stone, D. M., Pritchard, S. M. & Cantor, G. H. Bovine leukemia virus gp30 transmembrane (TM) protein is not tyrosine phosphorylated: examining potential interactions with host tyrosine-mediated signaling. Virus Res. 90, 155–169 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Pancholi, P., Mirza, A., Bhardwaj, N. & Steinman, R. M. Sequestration from immune CD4+ T cells of mycobacteria growing in human macrophages. Science 260, 984–986 (1993).

    Article  CAS  PubMed  Google Scholar 

  80. Wojciechowski, W., DeSanctis, J., Skamene, E. & Radzioch, D. Attenuation of MHC class II expression in macrophages infected with Mycobacterium bovis bacillus Calmette–Guerin involves class II transactivator and depends on the Nramp1 gene. J. Immunol. 163, 2688–2696 (1999).

    CAS  PubMed  Google Scholar 

  81. Mariotti, S. et al. Mycobacterium tuberculosis subverts the differentiation of human monocytes into dendritic cells. Eur. J. Immunol. 32, 3050–3058 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Stenger, S., Niazi, K. R. & Modlin, R. L. Down-regulation of CD1 on antigen-presenting cells by infection with Mycobacterium tuberculosis. J. Immunol. 161, 3582–3588 (1998).

    CAS  PubMed  Google Scholar 

  83. Noss, E. H. et al. Toll-like receptor 2-dependent inhibition of macrophage class II MHC expression and antigen processing by 19-kDa lipoprotein of Mycobacterium tuberculosis. J. Immunol. 167, 910–918 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Pai, R. K., Convery, M., Hamilton, T. A., Boom, W. H. & Harding, C. V. Inhibition of IFN-γ-induced class II transactivator expression by a 19-kDa lipoprotein from Mycobacterium tuberculosis: a potential mechanism for immune evasion. J. Immunol. 171, 175–184 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Hakansson, S., Galyov, E. E., Rosqvist, R. & Wolf-Watz, H. The Yersinia YpkA Ser/Thr kinase is translocated and subsequently targeted to the inner surface of the HeLa cell plasma membrane. Mol. Microbiol. 20, 593–603 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Galyov, E. E., Hakansson, S., Forsberg, A. & Wolf-Watz, H. A secreted protein kinase of Yersinia pseudotuberculosis is an indispensable virulence determinant. Nature 361, 730–732 (1993).

    Article  CAS  PubMed  Google Scholar 

  87. Cole, S. T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998). A landmark paper in mycobacteriology, as it led to the identification of several potential mycobacterial drug targets, including several serine/threonine protein kinases and tyrosine phosphatases.

    Article  CAS  PubMed  Google Scholar 

  88. Chaba, R., Raje, M. & Chakraborti, P. K. Evidence that a eukaryotic-type serine/threonine protein kinase from Mycobacterium tuberculosis regulates morphological changes associated with cell division. Eur. J. Biochem. 269, 1078–1085 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Av-Gay, Y., Jamil, S. & Drews, S. J. Expression and characterization of the Mycobacterium tuberculosis serine/threonine protein kinase PknB. Infect. Immun. 67, 5676–5682 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Peirs, P., de Wit, L., Braibant, M., Huygen, K. & Content, J. A serine/threonine protein kinase from Mycobacterium tuberculosis. Eur. J. Biochem. 244, 604–612 (1997).

    Article  CAS  PubMed  Google Scholar 

  91. Koul, A. et al. Serine/threonine protein kinases PknF and PknG of Mycobacterium tuberculosis: characterization and localization. Microbiology 147, 2307–2314 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Eiglmeier, K. et al. The decaying genome of Mycobacterium leprae. Lepr. Rev. 72, 387–398 (2001).

    CAS  PubMed  Google Scholar 

  93. Sassetti, C. M., Boyd, D. H. & Rubin, E. J. Genes required for mycobacterial growth defined by high density mutagenesis. Mol. Microbiol. 48, 77–84 (2003). These authors characterized the genes essential for mycobacterial growth using a technique involving random mutagenesis of the mycobacterial genome with transposons. They identified several STPKs as essential for mycobacterial growth in vitro.

    Article  CAS  PubMed  Google Scholar 

  94. Av-Gay, Y., Drews, S. J. & Cowley, S. Tuberculosis drug targets. PCT WO-03/074728–A2 (2003).

  95. Kennelly, P. J. & Potts, M. Fancy meeting you here! A fresh look at 'prokaryotic' protein phosphorylation. J. Bacteriol. 178, 4759–4764 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Persson, C., Carballeira, N., Wolf-Watz, H. & Fallman, M. The PTPase YopH inhibits uptake of Yersinia, tyrosine phosphorylation of p130cas and FAK, and the associated accumulation of these proteins in peripheral focal adhesions. EMBO J. 16, 2307–2318 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Black, D. S. & Bliska, J. B. Identification of p130cas as a substrate of Yersinia YopH (Yop51), a bacterial protein tyrosine phosphatase that translocates into mammalian cells and targets focal adhesions. EMBO J. 16, 2730–2744 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Fu, Y. & Galan, J. E. A salmonella protein antagonizes Rac-1 and Cdc42 to mediate host-cell recovery after bacterial invasion. Nature 401, 293–297 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Koul, A. et al. Cloning and characterization of secretory tyrosine phosphatases of Mycobacterium tuberculosis. J. Bacteriol. 182, 5425–5432 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Singh, R. et al. Disruption of mptpB impairs the ability of Mycobacterium tuberculosis to survive in guinea pigs. Mol. Microbiol. 50, 751–762 (2003). This paper describes, for the first time, the role of protein tyrosine phosphatases in the pathogenesis of M. tuberculosis and possible implications for interaction with IFN-γ signalling pathways in host cells.

    Article  CAS  PubMed  Google Scholar 

  101. Stewart, G., Robertson, B. D. & Young, D. B. Tuberculosis: A problem with persistence. Nature Rev. Microbiol. 1, 97–105 (2003)

    Article  CAS  Google Scholar 

  102. Shawver, L. K., Slamon, D. & Ullrich, A. Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 1, 117–123 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Prabhakaran, K., Harris, E. B. & Randhawa, B. Regulation by protein kinase of phagocytosis of Mycobacterium leprae by macrophages. J. Med. Microbiol. 49, 339–342 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Drews, S. J., Hung, F. & Av-Gay, Y. A protein kinase inhibitor as an antimycobacterial agent. FEMS Microbiol. Lett. 205, 369–374 (2001). This is an excellent demonstration of the use of kinase inhibitors as antimycobacterial agents.

    Article  CAS  PubMed  Google Scholar 

  105. Young, T. A., Delagoutte, B., Endrizzi, J. A., Falick, A. M. & Alber, T. Structure of Mycobacterium tuberculosis PknB supports a universal activation mechanism for Ser/Thr protein kinases. Nature Struct. Biol. (2003).

  106. Muller, G. Medicinal chemistry of target family-directed masterkeys. Drug Discov. Today 8, 681–691 (2003).

    Article  PubMed  Google Scholar 

  107. Stock, A. M., Robinson, V. L. & Goudreau, P. N. Two-component signal transduction. Annu. Rev. Biochem. 69, 183–215 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Zahrt, T. C. & Deretic, V. Mycobacterium tuberculosis signal transduction system required for persistent infections. Proc. Natl Acad. Sci. USA 98, 12706–12711 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Parish, T., Smith, D. A., Roberts, G., Betts, J. & Stoker, N. G. The senX3-regX3 two-component regulatory system of Mycobacterium tuberculosis is required for virulence. Microbiology 149, 1423–1435 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Johnson, T. O., Ermolieff, J. & Jirousek, M. R. Protein tyrosine phosphatase 1B inhibitors for diabetes. Nature Rev. Drug Discov. 1, 696–709 (2002).

    Article  CAS  Google Scholar 

  111. Chen, Y. T. & Seto, C. T. Divalent and trivalent α-ketocarboxylic acids as inhibitors of protein tyrosine phosphatases. J. Med. Chem. 45, 3946–3952 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Smith, C. V., Sharma, V. & Sacchettini, J. C. TB drug discovery: addressing issues of persistence and resistance. Tuberculosis 84, 45–55 (2004).

    Article  PubMed  Google Scholar 

  113. Khasnobis, S., Escuyer, V. E. & Chatterjee, D. Emerging therapeutic targets in tuberculosis: post-genomic era. Expert. Opin. Ther. Targets. 6, 21–40 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Barry, C. E. Preclinical candidates and targets for tuberculosis therapy. Curr. Opin. Investig. Drugs 2, 198–201 (2001).

    CAS  PubMed  Google Scholar 

  115. Darwin, K. H., Ehrt, S., Gutierrez-Ramos, J. C., Weich, N. & Nathan, C. F. The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302, 1963–1966 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Weinrauch, Y. & Zychlinsky, A. The induction of apoptosis by bacterial pathogens. Annu. Rev. Microbiol. 53, 155–187 (1999).

    Article  CAS  PubMed  Google Scholar 

  118. Yrlid, U. & Wick, M. J. Salmonella-induced apoptosis of infected macrophages results in presentation of a bacteria-encoded antigen after uptake by bystander dendritic cells. J. Exp. Med. 191, 613–624 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Schaible, U. E. et al. Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nature Med. 9, 1039–1046 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to K. Drilica (Public Health Research Institute, New York, USA) and to G. Bacher, H. Daub and G. Müller (Axxima AG) for critical reading of the manuscript, and to Y. Av-Gay (University of British Columbia, Vancouver, Canada) and J. Pieters (University of Basel, Switzerland) for helpful conversations. Our thanks go to I. Bhattacharya (MPI-Martinsried, Germany) for help with the references and to our colleagues at Axxima for useful insights into mycobacterial drug development.

Author information

Authors and Affiliations

  1. Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, Munich, 81377, Germany

    Anil Koul, Thomas Herget & Bert Klebl

  2. Max-Planck Institute for Biochemistry, Am Klopferspitz 18A, Martinsried, 82152, Germany

    Axel Ullrich

Authors
  1. Anil Koul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Herget
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bert Klebl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Axel Ullrich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anil Koul.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

Mycobacterium bovis

Mycobacterium tuberculosis

Infectious Disease Information

Tuberculosis

LocusLink

IFN-γ

IL-10

MAPKs

PLC-γ2

TNF-α

SwissProt

Rab5

Rab7

SK

TLR2

TLR4

YopJ

FURTHER INFORMATION

Anil Koul's laboratory

Glossary

MACROPHAGES

Cells that belong to the mononuclear phagocyte system and are responsible for phagocytosis of foreign material.

PHAGOSOME

A vesicle that is formed by invagination of the plasma membrane during endocytosis and fuses with primary lysosomes to degrade engulfed material.

LYSOSOME

Membrane-limited cellular organelles with a low internal pH that contain acid hydrolases for the degradation of polymers such as proteins, RNA, DNA, polysaccharides and lipids.

INTERFERON

A cytokine that activates the innate immune response, thereby preventing replication of pathogens.

PHOSPHATIDYLINOSITOL-3-KINASE

(PI3K). PI3Ks are a conserved family of lipid kinases that phosphorylate the 3′-OH group of the inositol ring of membrane-bound phosphatidylinositides.

G-PROTEIN COUPLED RECEPTORS

(GPCRs). These cell surface receptors, which are characterized by seven transmembrane domains, are coupled to small G-proteins. Activation of GPCRs induces binding of GTP to the G-proteins, which leads to stimulation, or repression, of downstream signalling events.

NEUTROPHILS

Polynuclear leucocytes belonging to the myeloid lineage that migrate to sites of infection or wounds and mediate the inflammatory response.

CYTOKINES

Low-molecular-weight proteins that are important for immunity, inflammation and development, and which contribute to the pathophysiology of acute and chronic infections.

INNATE IMMUNE RESPONSE

A cellular defence reaction to counteract invading pathogens such as bacteria and viruses. It uses interferon-dependent signalling and leads to the activation of genes that are responsible for bactericidal or antiviral responses.

ISOGENIC

Having identical genotypes.

MORPHOTYPE

A member of one form of a polymorphic species.

CREB

cAMP response element (CRE)-binding protein. It stimulates the basal transcription of CRE-containing genes and mediates induction of transcription following phosphorylation by protein kinases.

ADAPTIVE IMMUNE RESPONSE

This involves specificity and immunological memory. It is mediated by T and B cells through activation of cytotoxic CD8+ T cells for pathogen killing, or by interaction with CD4+ T cells for antibody production.

GLYOXYLATE SHUNT

A biochemical pathway that is used by plants and microorganisms to metabolize acetate or long-chain fatty acids as a source of energy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koul, A., Herget, T., Klebl, B. et al. Interplay between mycobacteria and host signalling pathways. Nat Rev Microbiol 2, 189–202 (2004). https://doi.org/10.1038/nrmicro840

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro840

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing