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:

The role of transferrin-receptor variation in the host range of Trypanosoma brucei

Nature volume 391, pages 499–502 (1998)Cite this article

Abstract

Trypanosoma brucei1 is a unicellular parasite transmitted between African mammals by tsetse flies. T. brucei multiplies freely in the bloodstream of many different mammals, and survives by antigenic variation of the main component of its surface coat, variant surface glycoprotein (VSG)2,3. Trypanosomes take up transferrin through a heterodimeric transferrin receptor4,5,6,7,8,9, the genes for which are expressed in telomeric expression sites along with the VSG gene. There are up to 20 of these expression sites per trypanosome nucleus3,10,11,12,13,14,15, but usually only one is active at a time. Different expression sites encode transferrin receptors that are similar but not identical16. Here we show that these small differences between transferrin receptors can have profound effects on the binding affinity for transferrins from different mammals, and on the ability of trypanosomes to grow in the sera of these mammals. Our results suggest that the ability to switch between different transferrin-receptor genes allows T.brucei to cope with the large sequence diversity in the transferrins of its hosts17.

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: Schematic representation of a trypanosomal variant surface glycoprotein (VSG) gene expression site.
Figure 2: Effect of competing transferrins from various mammals on the uptake of 55Fe-labelled bovine transferrin by three different T. brucei 427 variants.
Figure 3: Growth characteristics of bloodstream trypanosome variant 221a on HMl-9 medium supplemented with 10% fetal calf serum or 10% canine serum.

Similar content being viewed by others

References

  1. Bruce, D. Preliminary Report on the Tsetse Fly Disease or Nagana, in Zululand (Bennett and Davis, Durban, 1895).

    Google Scholar 

  2. Cross, G. A. M. Identification, purification and properties of clone-specific glycoprotein antigens constituting the surface coat of Trypanosoma brucei. Parasitology 71, 393–417 (1975).

    Article  CAS  Google Scholar 

  3. Cross, G. A. M. Cellular and genetic aspects of antigenic variations in trypanosomes. Annu. Rev. Immunol. 8, 83–110 (1990).

    Article  CAS  Google Scholar 

  4. Ligtenberg, M. J.et al. Reconstitution of a surface transferrin binding complex in insect form Trypanosoma brucei. EMBO J. 13, 2565–2573 (1994).

    Article  CAS  Google Scholar 

  5. Steverding, D.et al. ESAG 6 and 7 products of Trypanosoma brucei form a transferrin binding protein complex. Eur. J. Cell Biol. 64, 78–87 (1994).

    CAS  PubMed  Google Scholar 

  6. Chaudhri, M., Steverding, D., Kittelberger, D., Tija, S. & Overath, P. Expression of a glycosylphosphatidylinositol-anchored Trypanosoma brucei transferrin-bindign protein complex in insect cells. Proc. Natl Acad. Sci. USA 91, 6443–6447 (1994).

    Article  ADS  CAS  Google Scholar 

  7. Salmon, D.et al. Anovel heterodimeric transferrin receptor encoded by a pair of VSG expression site-associated genes in T. brucei. Cell 78, 75–86 (1994).

    Article  CAS  Google Scholar 

  8. Borst, P. Molecular genetics of antigenic variation. Immunol. Today 12, A29–A33 (1991).

    Article  CAS  Google Scholar 

  9. Schell, D.et al. Atransferrin-binding protein of Trypanosoma brucei is encoded by one of the genes in the variant surface glycoprotein expression site. EMBO J. 10, 1061–1066 (1991).

    Article  CAS  Google Scholar 

  10. Cully, D. F., Ip, H. S. & Cross, G. A. M. Coordinate transcription of variant surface glycoprotein genes and an expression site associated gene family in Trypanosoma brucei. Cell 42, 173–182 (1985).

    Article  CAS  Google Scholar 

  11. Pays, E.et al. The genes and transcripts of an antigen gene expression site from T. brucei. Cell 57, 835–845 (1989).

    Article  CAS  Google Scholar 

  12. Lips, S., Revelard, P. & Pays, E. Identification of a new expression site-associated gene in the complete 30.5 kb sequence from the AnTat 1.3A variant surface protein gene expression site of Trypanosoma brucei. Mol. Biochem. Parasitol. 62, 135–137 (1993).

    Article  CAS  Google Scholar 

  13. Borst, P. & Rudenko, G. Antigenic variation in African trypanosomes. Science 264, 1872–1874 (1994).

    Article  ADS  CAS  Google Scholar 

  14. Pays, E., Vanhamme, L. & Berberof, M. Genetic controls for the expression of surface antigens in African trypanosomes. Annu. Rev. Microbiol. 48, 25–52 (1994).

    Article  CAS  Google Scholar 

  15. Donelson, J. E. Mechanisms of antigenic variation in Borrelia hermsii and African trypanosomes. J. Biol. Chem. 270, 7783–7786 (1995).

    Article  CAS  Google Scholar 

  16. Zomerdijk, J. C., Kieft, R., Duyndam, M., Shiels, P. G. & Borst, P. Antigenic variation in Trypanosoma brucei: a telomeric expression site for variant-specific surface glycoprotein genes with novel features. Nucleic Acids Res. 19, 1359–1368 (1991).

    Article  CAS  Google Scholar 

  17. Retzer, M. D., Kabani, A., Button, L. L., Yu, R. H. & Schryvers, A. B. Production and characterization of chimeric transferrins for the determination of the binding domains for bacterial transferrin receptors. J. Biol. Chem. 271, 1166–1173 (1996).

    Article  CAS  Google Scholar 

  18. Enns, C. A. & Sussmann, H. H. Similarities between the transferrin receptor proteins on human reticulocytes and human placentae. J. Biol. Chem. 256, 12620–12623 (1981).

    CAS  PubMed  Google Scholar 

  19. Steverding, D., Stierhof, Y. D., Fuchs, H., Tauber, R. & Overath, P. The TFBP-complex is the receptor for transferrin uptake in Trypanosoma brucei. J. Cell Biol. 131, 1173–1182 (1995).

    Article  CAS  Google Scholar 

  20. Borst, P. Transferrin receptor, antigenic variation and the prospect of a trypanosome vaccine. Trends Genet. 7, 307–309 (1991).

    Article  CAS  Google Scholar 

  21. Young, P. & Garner, C. Delivery of iron to human cells by bovine transferrin. Biochem. J. 265, 587–591 (1990).

    Article  CAS  Google Scholar 

  22. Voest, E. E., Rooth, H., Neijt, J. P., van Asbeck, B. S. & Marx, J. J. The in vitro response of human tumour cells to desferrioxamine is growth medium dependent. Cell Prolif. 26, 77–88 (1993).

    Article  CAS  Google Scholar 

  23. Rudenko, G., Blundell, P. A., Dirks-Mulder, A., Kieft, R. & Borst, P. Aribosomal DNA promoter replacing the promoter of a telomeric Variant Surface Glycoprotein gene expression site can be efficiently switched on and off in Trypanosoma brucei. Cell 83, 547–553 (1995).

    Article  CAS  Google Scholar 

  24. Hobbs, M. R. & Boothroyd, J. C. An expression-site-associated gene family of trypanosomes is expressed in vivo and shows homology to a variant surface glycoprotein gene. Mol. Biochem. Parasitol. 43, 1–16 (1990).

    Article  CAS  Google Scholar 

  25. Liu, A. Y., Michels, P. A., Bernards, A. & Borst, P. Trypanosome variant surface glycoprotein genes expressed early in infection. J. Mol. Biol. 182, 383–396 (1985).

    Article  CAS  Google Scholar 

  26. Borst, P.et al. Trypanosomiasis and Leishmaniasis: biology and control, Vol. 1(eds Hide, G., Mottram, J. C., Coombs, G. H. & Holmes, P. H.) 109–131 (British Society for Parasitology/CAB International, Oxford, 1997).

    Google Scholar 

  27. Hirumi, H. & Hirumi, K. Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. J. Parasitol. 75, 985–989 (1989).

    Article  CAS  Google Scholar 

  28. Brun, R. & Schönenberger, M. Cultivation and in vitro cloning of procyclic culture forms of Trypanosoma brucei in a semi defined medium. Acta Tropica 36, 389–292 (1979).

    Google Scholar 

  29. Uriel, J., Poupon, M. F. & Geuskens, M. Alphafoetoprotein uptake by cloned cell lines derived from a nickel-induced rat rhabdomyosarcoma. Br. J. Cancer 48, 261–269 (1983).

    Article  CAS  Google Scholar 

  30. Revelard, P., Lips, S. & Pays, E. Agene from the VSG expression site of Trypanosoma brucei encodes a protein with both leucine-rich repeats and a putative zinc finger. Nucleic Acids Res. 18, 7299–7303 (1990).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. Blundell, F. van Leeuwen, M. Cross, R. McCulloch, M. Ligtenberg, R.Plasterk, G. Rudenko, A. Schinkel and E. J. J. van Zoelen for advice and comments on the manuscript. This work was supported in part by a grant from the Netherlands Foundation for Chemical Research (SON) and financial aid from the Netherlands Organization for Scientific Research (NWO).

Author information

Author notes

  1. W. Bitter

    Present address: Department of Molecular Cell Biology, Utrecht University, P.O. Box 80 056, 3508, TB Utrecht, The Netherlands

Authors and Affiliations

  1. Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    H. Gerrits, R. Kieft & P. Borst

Authors
  1. W. Bitter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Gerrits
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Kieft
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Borst
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bitter, W., Gerrits, H., Kieft, R. et al. The role of transferrin-receptor variation in the host range of Trypanosoma brucei. Nature 391, 499–502 (1998). https://doi.org/10.1038/35166

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35166

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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