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.

  • Letter
  • Published:

Mycobactin-mediated iron acquisition within macrophages

Nature Chemical Biology volume 1, pages 149–153 (2005)Cite this article

Abstract

Restricting the availability of iron is an important strategy for defense against bacterial infection1,2,3. Mycobacterium tuberculosis survives within the phagosomes of macrophages; consequently, iron acquisition is particularly difficult for M. tuberculosis, because the phagosomal membrane is an additional barrier for its iron access4,5. However, little is known about the iron transport and acquisition pathways adapted by this microbe in vivo6. Extracellular iron sources are usually mobilized by hydrophilic siderophores7,8. Here, we describe direct evidence that mycobactins, the lipophilic siderophores of mycobacteria, efficiently extract intracellular macrophage iron. The metal-free siderophore is diffusely associated with the macrophage membrane, ready for iron chelation. Notably, the mycobactin-metal complex accumulates with high selectivity in macrophage lipid droplets, intracellular domains for lipid storage and sorting9,10. In our experiments, these mycobactin-targeted lipid droplets were found in direct contact with phagosomes, poised for iron delivery. The existence of this previously undescribed iron acquisition pathway indicates that mycobacteria have taken advantage of endogenous macrophage mechanisms for iron mobilization and lipid sorting for iron acquisition during infection. The pathway could represent a new target for the control of mycobacterial infection.

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: MJ-mediated iron acquisition.
Figure 2: Membrane partitioning of MJ and Fe-MJ.
Figure 3: Distribution patterns of MJ and Ga-MJ within macrophages.
Figure 4: Our proposed MJ-mediated iron-acquisition pathway for macrophage-niched mycobacteria.

Similar content being viewed by others

References

  1. Flo, T.H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).

    Article  CAS  Google Scholar 

  2. Ferreras, J.A., Ryu, J.S., Lello, F.D., Tan, D.S. & Quadri, L.E.N. Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat. Chem. Bio. 1, 29–32 (2005).

    Article  CAS  Google Scholar 

  3. Fluckinger, M., Hass, H., Merschak, P., Glasgow, B.J. & Redl, B. Human tear lipocalin exhibits antimicrobial activity by scavenging microbial siderophores. Antimicrob. Agents Chemother. 48, 3367–3372 (2004).

    Article  CAS  Google Scholar 

  4. Pieters, J. Entry and survival of pathogenic mycobacteria in macrophages. Microbes Infect. 3, 249–255 (2001).

    Article  CAS  Google Scholar 

  5. Rhoades, E.R. & Ullrich, H.J. How to establish a lasting relationship with your host: lessons learned from Mycobacterium spp. Immunol. Cell Biol. 78, 301–310 (2000).

    Article  CAS  Google Scholar 

  6. Schaible, U.E. & Kaufmann, S.H.E. Iron and microbial infection. Nat. Rev. Microbiol. 2, 946–953 (2004).

    Article  CAS  Google Scholar 

  7. Albrecht-Gary, A.M. & Crumbliss, A.L. Coordination chemistry of siderophores: thermodynamics and kinetics of iron chelation and release. Met. Ions Biol. Syst. 35, 239–327 (1998).

    CAS  PubMed  Google Scholar 

  8. Ratledge, C. & Dover, L.G. Iron metabolism in pathogenic bacteria. Annu. Rev. Microbiol. 54, 881–941 (2000).

    Article  CAS  Google Scholar 

  9. Melo, R.C., D'Avila, H., Fabrino, D.L., Almeida, P.E. & Bozza, P.T. Macrophage lipid body induction by Chagas disease in vivo: putative intracellular domains for eicosanoid formation during infection. Tissue Cell 35, 59–67 (2003).

    Article  CAS  Google Scholar 

  10. Yu, W. et al. Co-compartmentalization of MAP kinases and cytosolic phospholipase A(2) at cytoplasmic arachidonate-rich lipid bodies. Am. J. Pathol. 152, 759–769 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Burke, B. & Lewis, C.E. The Macrophage (Oxford University Press, Oxford, UK, 2002).

    Google Scholar 

  12. Torti, S.V. et al. The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor-inducible gene. J. Biol. Chem. 263, 12638–12644 (1988).

    CAS  PubMed  Google Scholar 

  13. Byrd, T.F. & Horwitz, M.A. Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma. J. Clin. Invest. 91, 969–976 (1993).

    Article  CAS  Google Scholar 

  14. Weiss, G., Wachter, H. & Fuchs, D. Linkage of cell-mediated immunity to iron metabolism. Immunol. Today 16, 495–500 (1995).

    Article  CAS  Google Scholar 

  15. Vergne, A.F., Walz, A.J. & Miller, M.J. Iron chelators from mycobacteria (1954–1999) and potential therapeutic applications. Nat. Prod. Rep. 17, 99–116 (2000).

    Article  CAS  Google Scholar 

  16. Olakanmi, O., Schlesinger, L.S., Ahmed, A. & Britigan, B.E. Intraphagosomal Mycobacterium tuberculosis acquires iron from both extracellular transferrin and intracellular iron pools. Impact of interferon-gamma and hemochromatosis. J. Biol. Chem. 277, 49727–49734 (2002).

    Article  CAS  Google Scholar 

  17. Sun, H., Li, H.Y. & Sadler, P.J. Transferrin as a metal ion mediator. Chem. Rev. 99, 2817–2842 (1999).

    Article  CAS  Google Scholar 

  18. Fadeev, E.A., Luo, M. & Groves, J.T. Synthesis, structure, and molecular dynamics of gallium complexes of schizokinen and the amphiphilic siderophore acinetoferrin. J. Am. Chem. Soc. 126, 12065–12075 (2004).

    Article  CAS  Google Scholar 

  19. Murphy, D.J. The biogenesis and functions of lipid bodies in animals, plants and microorganisms. Prog. Lipid Res. 40, 325–438 (2001).

    Article  CAS  Google Scholar 

  20. Dvorak, A.M. et al. Lipid bodies: cytoplasmic organelles important to arachidonate metabolism in macrophages and mast cells. J. Immunol. 131, 2965–2976 (1983).

    CAS  PubMed  Google Scholar 

  21. De Voss, J.J. et al. The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages. Proc. Natl. Acad. Sci. USA 97, 1252–1257 (2000).

    Article  CAS  Google Scholar 

  22. Xu, G., Martinez, J.S., Groves, J.T. & Butler, A. Membrane affinity of the amphiphilic marinobactin siderophores. J. Am. Chem. Soc. 124, 13408–13415 (2002).

    Article  CAS  Google Scholar 

  23. Luo, M., Fadeev, E.A. & Groves, J.T. Membrane dynamics of the amiphiphilic siderophore, acinetoferrin. J. Am. Chem. Soc. 127, 1726–1736 (2005).

    Article  CAS  Google Scholar 

  24. Moody, D.B. et al. T cell activation by lipopeptide antigens. Science 303, 527–531 (2004).

    Article  CAS  Google Scholar 

  25. Testa, U. et al. Iron up-modulates the expression of transferrin receptors during monocyte-macrophage maturation. J. Biol. Chem. 264, 13181–13187 (1989).

    CAS  PubMed  Google Scholar 

  26. Mulero, V. & Brock, J.H. Regulation of iron metabolism in murine J774 macrophages: role of nitric oxide-dependent and independent pathways following activation with gamma interferon and lipopolysaccharide. Blood 94, 2383–2389 (1999).

    CAS  PubMed  Google Scholar 

  27. Crosa, J.H. & Walsh, C.T. Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol. Mol. Biol. Rev. 66, 223–249 (2002).

    Article  CAS  Google Scholar 

  28. De Voss, J.J., Rutter, K., Schroeder, B.G. & Barry, C.E. Iron acquisition and metabolism by mycobacteria. J. Bacteriol. 181, 4443–4451 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ratledge, C. Iron, mycobacteria and tuberculosis. Tuberculosis (Edinb.) 84, 110–130 (2004).

    Article  Google Scholar 

  30. Olakanmi, O., Britigan, B.E. & Schlesinger, L.S. Gallium disrupts iron metabolism of mycobacteria residing within human macrophages. Infect. Immun. 68, 5619–5627 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank M. Marlow for providing facilities and technical assistance with cell cultures, J. Goodhouse for fluorescent confocal microscopy and F. Morel and B. Ward for iron-labeling experiments. Support of this work by the US National Science Foundation (CHE-0221978) through the Environmental Molecular Science Institute (CEBIC) at Princeton University is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Chemistry, Princeton University, Princeton, 08544, New Jersey, USA

    Minkui Luo, Evgeny A Fadeev & John T Groves

Authors
  1. Minkui Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Evgeny A Fadeev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John T Groves
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John T Groves.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, M., Fadeev, E. & Groves, J. Mycobactin-mediated iron acquisition within macrophages. Nat Chem Biol 1, 149–153 (2005). https://doi.org/10.1038/nchembio717

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio717

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