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:

Transmission of cutaneous leishmaniasis by sand flies is enhanced by regurgitation of fPPG

Nature volume 430, pages 463–467 (2004)Cite this article

Abstract

Sand flies are the exclusive vectors of the protozoan parasite Leishmania1, but the mechanism of transmission by fly bite has not been determined nor incorporated into experimental models of infection. In sand flies with mature Leishmania infections the anterior midgut is blocked by a gel of parasite origin, the promastigote secretory gel2,3. Here we analyse the inocula from Leishmania mexicana-infected Lutzomyia longipalpis sand flies. Analysis revealed the size of the infectious dose, the underlying mechanism of parasite delivery by regurgitation, and the novel contribution made to infection by filamentous proteophosphoglycan (fPPG), a component of promastigote secretory gel found to accompany the parasites during transmission. Collectively these results have important implications for understanding the relationship between the parasite and its vector, the pathology of cutaneous leishmaniasis in humans and also the development of effective vaccines and drugs. These findings emphasize that to fully understand transmission of vector-borne diseases the interaction between the parasite, its vector and the mammalian host must be considered together.

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: Sand flies make a significant contribution to transmission and egest exacerbation factors.
Figure 2: The fPPG component of Leishmania PSG is egested by infected sand flies.
Figure 3: PSG enhances L. mexicana disease progression more than saliva.
Figure 4: The fPPG fraction of PSG is responsible for enhancement of Leishmania infectivity.

Similar content being viewed by others

References

  1. Sacks, D. L. & Kamhawi, S. Molecular aspects of parasite-vector and vector-host interactions in leishmaniasis. Annu. Rev. Microbiol. 55, 453–483 (2001)

    Article  CAS  Google Scholar 

  2. Stierhof, Y.-D. et al. Filamentous proteophosphoglycan secreted by Leishmania promastigotes forms gel-like three-dimensional networks that obstruct the digestive tract of infected sandfly vectors. Eur. J. Cell Biol. 78, 675–689 (1999)

    Article  CAS  Google Scholar 

  3. Rogers, M. E., Chance, M. L. & Bates, P. A. The role of promastigote secretory gel in the origin and transmission of the infective stage of Leishmania mexicana by the sandfly Lutzomyia longipalpis. Parasitol. 124, 495–507 (2002)

    Article  CAS  Google Scholar 

  4. UNDP/World Bank/WHO. Leishmaniasis 〈http://www.who.int/tdr/diseases/leish/diseaseinfo.htm〉 (2004).

  5. Sacks, D. L. & Perkins, P. V. Identification of an infective stage of Leishmania promastigotes. Science 223, 1417–1419 (1984)

    Article  ADS  CAS  Google Scholar 

  6. Titus, R. G. & Ribeiro, J. M. Salivary gland lysates from the sand fly Lutzomyia longipalpis enhance Leishmania infectivity. Science 239, 1306–1308 (1988)

    Article  ADS  CAS  Google Scholar 

  7. Belkaid, Y. et al. Development of a natural model of cutaneous leishmaniasis: powerful effects of vector saliva and saliva preexposure on the long-term outcome of Leishmania major infection in the mouse ear dermis. J. Exp. Med. 188, 1941–1953 (1998)

    Article  CAS  Google Scholar 

  8. Schlein, Y., Jacobson, R. L. & Messer, G. Leishmania infections damage the feeding mechanism of the sandfly vector and implement parasite transmission by bite. Proc. Natl Acad. Sci. USA 89, 9944–9948 (1992)

    Article  ADS  CAS  Google Scholar 

  9. Pimenta, P. F. et al. Stage-specific adhesion of Leishmania promastigotes to the sandfly midgut. Science 256, 1812–1815 (1992)

    Article  ADS  CAS  Google Scholar 

  10. Sacks, D. L. et al. The role of phosphoglycans in Leishmania-sand fly interactions. Proc. Natl Acad. Sci. USA 97, 406–411 (2000)

    Article  ADS  CAS  Google Scholar 

  11. Späth, G. F. et al. Lipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major. Proc. Natl Acad. Sci. USA 97, 9258–9263 (2000)

    Article  ADS  Google Scholar 

  12. Späth, G. F. et al. Persistence without pathology in phosphoglycan-deficient Leishmania major. Science 301, 1241–1243 (2003)

    Article  ADS  Google Scholar 

  13. Ilg, T. et al. Purification and structural characterization of a filamentous, mucin-like proteophosphoglycan secreted by Leishmania parasites. J. Biol. Chem. 271, 21583–21596 (1996)

    Article  CAS  Google Scholar 

  14. Ilg, T. Proteophosphoglycans of Leishmania. Trends Parasitol. 16, 489–497 (2000)

    CAS  Google Scholar 

  15. Warburg, A. & Schlein, Y. The effect of post-bloodmeal nutrition of Phlebotomus papatasi on the transmission of Leishmania major. Am. J. Trop. Med. Hyg. 35, 926–930 (1986)

    Article  CAS  Google Scholar 

  16. Saraiva, E. M. B. et al. Changes in lipophosphoglycan and gene expression associated with the development of Leishmania major in Phlebotomus papatasi. Parasitol. 111, 275–287 (1995)

    Article  CAS  Google Scholar 

  17. Kamhawi, S., Belkaid, Y., Modi, G., Rowton, E. & Sacks, D. L. Protection against cutaneous leishmaniasis resulting from bites of uninfected sand flies. Science 290, 1351–1354 (2000)

    Article  ADS  CAS  Google Scholar 

  18. Castro-Sousa, F. et al. Dissociation between vasodilation and Leishmania-enhancing effects of sand fly saliva and maxadilan. Mem. Inst. Oswaldo Cruz 96, 997–999 (2001)

    Article  CAS  Google Scholar 

  19. Wiese, M., Ilg, T., Lottspeich, F. & Overath, P. Ser/Thr-rich repetitive motifs as targets for phosphoglycan modifications in Leishmania mexicana secreted acid phosphatase. EMBO J. 14, 1067–1074 (1995)

    Article  CAS  Google Scholar 

  20. Gopfert, U. et al. Proteophosphoglycans of Leishmania mexicana. Molecular characterization of the Leishmania mexicana ppg2 gene encoding the protephosphoglycans aPPG and pPPG2 that are secreted by amastigotes and promastigotes. Biochem. J. 344, 787–795 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ilg, T. Lipophosphoglycan is not required for infection of macrophages or mice by Leishmania mexicana. EMBO J. 19, 1953–1962 (2000)

    Article  CAS  Google Scholar 

  22. Ilg, T., Demar, M. & Harbecke, D. Phosphoglycan repeat-deficient Leishmania mexicana parasites remain infectious to macrophages and mice. J. Biol. Chem. 276, 4988–4997 (2001)

    Article  CAS  Google Scholar 

  23. Nikolaev, A. V., Chudek, J. A. & Ferguson, M. A. J. The chemical synthesis of Leishmania donovani phosphoglycan via polycondensation of a glycobiosyl hydrogen phosphonate monomer. Carbohydr. Res. 272, 179–189 (1995)

    Article  CAS  Google Scholar 

  24. Beach, R., Kiilu, G. & Leeuwenburg, J. Modification of sandfly biting behaviour by Leishmania leads to increased parasite transmission. Am. J. Trop. Med. Hyg. 34, 278–282 (1985)

    Article  CAS  Google Scholar 

  25. Hertig, M. & McConnell, E. Experimental infection of Panamanian Phlebotomus sandflies with Leishmania. Exp. Parasitol. 14, 92–106 (1963)

    Article  CAS  Google Scholar 

  26. Bates, P. A. & Tetley, L. Leishmania mexicana: induction of metacyclogenesis by cultivation of promastigotes at acidic pH. Exp. Parasitol. 76, 412–423 (1993)

    Article  CAS  Google Scholar 

  27. Ilg, T., Harbecke, D., Wiese, M. & Overath, P. Monoclonal antibodies directed against Leishmania secreted acid phosphatase and lipophosphoglycan. Eur. J. Biochem. 217, 603–615 (1993)

    Article  CAS  Google Scholar 

  28. Bates, P. A., Hermes, I. & Dwyer, D. M. Golgi-mediated post-translational processing of secretory acid phosphatase by Leishmania donovani promastigotes. Mol. Biochem. Parasitol. 39, 247–256 (1990)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The technical assistance of D. Moor and J. Archer is acknowledged. We thank M. Hajmova and P. Volf for assistance with the forced feeding technique and M. Wiese and P. Overath for antibodies and Leishmania mutants. This work received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) and the Wellcome Trust, UK.

Author information

Author notes

  1. Thomas Ilg

    Present address: Intervet Innovation GmbH, Zur Propstei, 55270, Schwabenheim, Germany

Authors and Affiliations

  1. Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, L3 5QA, Liverpool, UK

    Matthew E. Rogers & Paul A. Bates

  2. Max-Planck-Institut fur Biologie, Abteilung Membranbiochemie, Corrensstrasse 38, 72076, Tubingen, Germany

    Thomas Ilg

  3. Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, The Wellcome Trust Biocentre, University of Dundee, DD1 5EH, Dundee, UK

    Andrei V. Nikolaev & Michael A. J. Ferguson

Authors
  1. Matthew E. Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Ilg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrei V. Nikolaev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael A. J. Ferguson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul A. Bates
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul A. Bates.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

Sand fly saliva is present but not adsorbed from egestion medium by DEAE-Sepharose. (PDF 114 kb)

Supplementary Figure 2

Leishmania mexicana lipophosphoglycan (LPG) is not a component of PSG or found free in the sand fly gut. (PDF 88 kb)

Supplementary Figure 3

Further evidence that the fPPG fraction of PSG is responsible for enhancement of Leishmania infectivity. (PDF 152 kb)

Supplementary Figure 4

Culture-derived and sand fly egested Leishmania mexicana metacyclic promastigotes are of equal infectivity. (PDF 50 kb)

Supplementary Figure 5

Sand fly salivary gland homogenate results in more disease exacerbation than saliva. (PDF 52 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rogers, M., Ilg, T., Nikolaev, A. et al. Transmission of cutaneous leishmaniasis by sand flies is enhanced by regurgitation of fPPG. Nature 430, 463–467 (2004). https://doi.org/10.1038/nature02675

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02675

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