Résumés
Résumé
Le parasite du genre Leishmania est, selon les espèces, responsable de différentes pathologies et représente une cause importante de morbidité et de mortalité en médecine humaine et vétérinaire. Ce parasite intracellulaire est transmis par l’intermédiaire de la mouche des sables chez un hôte vertébré, où, après différentiation, il se multiplie dans les macrophages. Le séquençage du génome de l’espèce Leishmania major est quasiment terminé. Ces données de séquences s’avèrent une source inestimable pour des études transcriptomiques et protéomiques qui permettent de mieux comprendre le processus de différentiation du parasite, son interaction avec la cellule hôte et sa capacité à résister aux traitements conventionnels.
Summary
Leishmania is a protozoan parasite responsible for considerable morbidity worldwide. The pathologies caused by Leishmania infections are varying with the species. The ongoing determination of the Leishmania major genome sequence represents a milestone for Leishmania research. We discuss here the use of transcriptomics and proteomics to accelerate our understanding of key processes related to Leishmania biology. These two techniques should be useful to find genes and proteins that are expressed in a stage-specific manner and examples of the use of such techniques are provided. Both approaches will complement each others. Indeed, while a number of stage-specific genes have increased stable RNA levels, an even larger subset of the Leishmania amastigote genes are regulated at the level of translation. The availability of the Leishmania genome should also permit important advances in finding species-specific genes that could explain different pathologies. Functional genomic and proteomic approaches should also be useful for understanding the mechanisms of drug resistance in the parasite. The availability of both the Leishmania genome and of its human host or of the mouse animal model will facilitate large scale studies and increase our understanding of host-pathogen interactions.
Parties annexes
Références
- 1. Fleischmann RD, Adams MD, White O, et al. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 1995; 269: 496-512.
- 2. Gardner MJ, Hall N, Fung E, et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 2002; 419: 498-511.
- 3. Sacks D, Kamhawi S. Molecular aspects of parasite-vector and vector-host interactions in leishmaniasis. Annu Rev Microbiol 2001; 55: 453-83.
- 4. Herwaldt BL. Leishmaniasis. Lancet 1999; 354: 1191-9.
- 5. Magill AJ, Grogl M, Gasser RA, Jr., Sun W, Oster CN. Visceral infection caused by Leishmania tropica in veterans of Operation Desert Storm. N Engl J Med 1993; 328: 1383-7.
- 6. Britto C, Ravel C, Bastien P, et al. Conserved linkage groups associated with large-scale chromosomal rearrangements between Old World and New World Leishmania genomes. Gene 1998; 222: 107-17.
- 7. Myler PJ, Audleman L, deVos T, et al.Leishmania major Friedlin chromosome 1 has an unusual distribution of protein-coding genes. Proc Natl Acad Sci USA 1999; 96: 2902-6.
- 8. Clayton CE. Life without transcriptional control? From fly to man and back again. Embo J 2002; 21: 1881-8.
- 9. McKean PG, Denny PW, Knuepfer E, Keen JK, Smith DF. Phenotypic changes associated with deletion and overexpression of a stage-regulated gene family in Leishmania. Cell Microbiol 2001; 3: 511-23.
- 10. Sereno D, Lemesre JL. Axenically cultured amastigote forms as an in vitro model for investigation of antileishmanial agents. Antimicrob Agents Chemother 1997; 41: 972-6.
- 11. Lamontagne J, Papadopoulou B. Developmental regulation of spliced leader RNA gene in Leishmaniadonovani amastigotes is mediated by specific polyadenylation. J Biol Chem 1999; 274: 6602-9.
- 12. Wu Y, El Fakhry Y, Sereno D, Tamar S, Papadopoulou B. A new developmentally regulated gene family in Leishmania amastigotes encoding a homolog of amastin surface proteins. Mol Biochem Parasitol 2000; 110: 345-57.
- 13. Charest H, Zhang WW, Matlashewski G. The developmental expression of Leishmania donovani A2 amastigote-specific genes is post-transcriptionally mediated and involves elements located in the 3'-untranslated region. J Biol Chem 1996; 271: 17081-90.
- 14. Bellatin JA, Murray AS, Zhao M, McMaster WR. Leishmania mexicana: identification of genes that are preferentially expressed in amastigotes. Exp Parasitol 2002; 100: 44-53.
- 15. Schoolnik GK. Functional and comparative genomics of pathogenic bacteria. Curr Opin Microbiol 2002; 5: 20-6.
- 16. Rathod PK, Ganesan K, Hayward RE, Bozdech Z, DeRisi JL. DNA microarrays for malaria. Trends Parasitol 2002; 18: 39-45.
- 17. Diehl S, Diehl F, El-Sayed N, Clayton C, Hoheisel J. Analysis of stage-specific gene expression in the bloodstream and the procyclic form of Trypanosoma brucei using a genomic DNA-microarray. Mol Biochem Parasitol 2002; 123: 115.
- 18. Almeida R, Norrish A, Levick M, et al. From genomes to vaccines: Leishmania as a model. Philos Trans R Soc Lond B Biol Sci 2002; 357: 5-11.
- 19. Beverley SM, Akopyants NS, Goyard S, et al. Putting the Leishmania genome to work: functional genomics by transposon trapping and expression profiling. Philos Trans R Soc Lond B Biol Sci 2002; 357: 47-53.
- 20. Talaat AM, Howard ST, Hale W 4th, Lyons R, Garner H, Johnston SA. Genomic DNA standards for gene expression profiling in Mycobacterium tuberculosis. Nucleic Acids Res 2002; 30: E104.
- 21. Chu S, DeRisi J, Eisen M, et al. The transcriptional program of sporulation in budding yeast. Science 1998; 282: 699-705.
- 22. Boucher N, Wu Y, Dumas C, et al. A common mechanism of stage-regulated gene expression in Leishmania mediated by a conserved 3'-untranslated region element. J Biol Chem 2002; 277: 19511-20.
- 23. El Fakhry Y, Ouellette M, Papadopoulou B. A proteomic approach to identify developmentally regulated proteins in Leishmania infantum. Proteomics 2002; 2: 1007-17.
- 24. Gygi SP, Rist B, Gerber SA, Turecek F, Gelb MH, Aebersold R. Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol 1999; 17: 994-9.
- 25. Washburn MP, Wolters D, Yates JR, 3rd. Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat Biotechnol 2001; 19: 242-7.
- 26. Zhang WW, Matlashewski G. Characterization of the A2-A2rel gene cluster in Leishmania donovani: involvement of A2 in visceralization during infection. Mol Microbiol 2001; 39: 935-48.
- 27. Carlton JM, Angiuoli SV, Suh BB, et al. Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii. Nature 2002; 419: 512-9.
- 28. Kündig C, Haimeur A, Légaré D, Papadopoulou B, Ouellette M. Increased transport of pteridines compensates for mutations in the high affinity folate transporter and contributes to methotrexate resistance in the protozoan parasite Leishmania tarentolae. Embo J 1999; 18: 2342-51.
- 29. Myler PJ, Beverley SM, Cruz AK, et al. The Leishmania genome project: new insights into gene organization and function. Med Microbiol Immunol(Berl) 2001; 190: 9-12.
- 30. Turco SJ, Descoteaux A. The lipophosphoglycan of Leishmania parasites. Annu Rev Microbiol 1992; 46: 65-94.
- 31. Matte C, Olivier M. Leishmania-induced cellular recruitment during the early inflammatory response: modulation of proinflammatory mediators. J Infect Dis 2002; 185: 673-81.
- 32. Pelletier I, Sato S. Specific recognition and cleavage of galectin-3 by Leishmaniamajor through species-specific polygalactose epitope. J Biol Chem 2002; 277: 17663-70.
- 33. Sato S. Galectin as a molecule of danger signal, which could evoke immune response to infection. Trends Glycosci Glycotechnol 2003 (sous presse).
- 34. Colmenares M, Puig-Kroger A, Pello OM, Corbi AL, Rivas L. Dendritic cell (DC)-specific Intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN, CD209), a C-type surface lectin in human DCs, is a receptor for Leishmania amastigotes. J Biol Chem 2002; 277: 36766-9.
- 35. Blanchette J, Racette N, Faure R, Siminovitch KA, Olivier M. Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-gamma-triggered JAK2 activation. Eur J Immunol 1999; 29: 3737-44.
- 36. Forget G, Siminovitch KA, Brochu S, Rivest S, Radzioch D, Olivier M. Role of host phosphotyrosine phosphatase SHP-1 in the development of murine leishmaniasis. Eur J Immunol 2001; 31: 3185-96.
- 37. Buates S, Matlashewski G. General suppression of macrophage gene expression during Leishmania donovani infection. J Immunol 2001; 166: 3416-22.
- 38. Matte C, Marquis JF, Blanchette J, et al. Peroxovanadium-mediated protection against murine leishmaniasis: role of the modulation of nitric oxide. Eur J Immunol 2000; 30: 2555-64.
- 39. Légaré D, Cayer S, Singh AK, Richard D, Papadopoulou B, Ouellette M. ABC proteins of Leishmania. J Bioenerg Biomembr 2001; 33: 469-74.
- 40. Haimeur A, Brochu C, Genest P, Papadopoulou B, Ouellette M. Amplification of the ABC transporter gene PGPA and increased trypanothione levels in potassium antimonyl tartrate (SbIII) resistant Leishmania tarentolae. Mol Biochem Parasitol 2000; 108: 131-5.
- 41. Légaré D, Richard D, Mukhopadhyay R, et al. The Leishmania ABC protein PGPA is an intracellular metal-thiol transporter ATPase. J Biol Chem 2001; 276: 26301-7.
- 42. Drummelsmith J, Brochu V, Girard I, Messier N, Ouellette M. Proteome mapping of the protozoan parasite Leishmania and application to the study of drug targets and resistance mechanisms. Mol Cell Proteomics 2003; 2: 146-55.
- 43. Dumas C, Ouellette M, Tovar J, et al. Disruption of the trypanothione reductase gene of Leishmania decreases its ability to survive oxidative stress in macrophages. Embo J 1997; 16: 2590-8.
- 44. Ullu E, Djikeng A, Shi H, Tschudi C. RNA interference: advances and questions. Philos Trans R Soc Lond B Biol Sci 2002; 357: 65-70.