User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure.

Primary tabs

Berg, Maya Vanaerschot, Manu Jankevics, Andris Cuypers, Bart Maes, Ilse Dujardin, Jean-Claude

Antimonial (sodium stibogluconate, SSG) resistance and differentiation have been shown to be closely linked in Leishmania donovani, with SSG-resistant strains showing an increased capacity to generate infectious (metacyclic) forms. This is the first untargeted LC-MS metabolomics study which integrated both phenomena in one experimental design and provided insights into metabolic differences between three clinical L. donovani strains with a similar genetic background but different SSG-susceptibilities. We performed this analysis at different stages during promastigote growth and in the absence or presence of drug pressure. When comparing SSG-resistant and SSG-sensitive strains, a number of metabolic changes appeared to be constitutively present in all growth stages, pointing towards a clear link with SSG-resistance, whereas most metabolic changes were only detected in the stationary stage. These changes reflect the close intertwinement between SSG-resistance and an increased metacyclogenesis in resistant parasites. The metabolic changes suggest that SSG-resistant parasites have (i) an increased capacity for protection against oxidative stress; (ii) a higher fluidity of the plasma membrane; and (iii) a metabolic survival kit to better endure infection. These changes were even more pronounced in a resistant strain kept under Sb(III) drug pressure.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2013
Language Anglais
Journal information "Molecular Microbiology" - Vol. 90, no. 2, p. 428-442
Peer reviewed yes
Publisher Wiley-Blackwell Publishing Ltd. ((United Kingdom) Chichester)
issn 0950-382X
e-issn 1365-2958
Publication status Publié
Affiliation UCL - SSS/DDUV - Institut de Duve
Links
  1. Allmann Stefan, Morand Pauline, Ebikeme Charles, Gales Lara, Biran Marc, Hubert Jane, Brennand Ana, Mazet Muriel, Franconi Jean-Michel, Michels Paul A. M., Portais Jean-Charles, Boshart Michael, Bringaud Frédéric, Cytosolic NADPH Homeostasis in Glucose-starved ProcyclicTrypanosoma bruceiRelies on Malic Enzyme and the Pentose Phosphate Pathway Fed by Gluconeogenic Flux, 10.1074/jbc.m113.462978
  2. Ashutosh, Sundar S., Goyal N., Molecular mechanisms of antimony resistance in Leishmania, 10.1099/jmm.0.46841-0
  3. BARRETT M, The pentose phosphate pathway and parasitic protozoa, 10.1016/s0169-4758(96)10075-2
  4. Bates Paul A, Leishmania sand fly interaction: progress and challenges, 10.1016/j.mib.2008.06.003
  5. Beez D., Sanchez C. P., Stein W. D., Lanzer M., Genetic Predisposition Favors the Acquisition of Stable Artemisinin Resistance in Malaria Parasites, 10.1128/aac.00916-10
  6. Berg, Parasitology, 12, 1 (2013)
  7. Berg M., Van der Veken P., Goeminne A., Haemers A., Augustyns K., Inhibitors of the Purine Salvage Pathway: A Valuable Approach for Antiprotozoal Chemotherapy?, 10.2174/092986710791556023
  8. Berg, Comp Struct Biotechnol J, 4, e201301002 (2012)
  9. Boitz Jan M., Ullman Buddy, Jardim Armando, Carter Nicola S., Purine salvage in Leishmania: complex or simple by design?, 10.1016/j.pt.2012.05.005
  10. Breitling Rainer, Bakker Barbara M., Barrett Michael P., Decuypere Saskia, Dujardin Jean-Claude, Metabolomic Systems Biology of Protozoan Parasites, Genetics Meets Metabolomics (2012) ISBN:9781461416883 p.73-84, 10.1007/978-1-4614-1689-0_6
  11. Chawla Bhavna, Jhingran Anupam, Panigrahi Aswini, Stuart Kenneth D., Madhubala Rentala, Paromomycin Affects Translation and Vesicle-Mediated Trafficking as Revealed by Proteomics of Paromomycin –Susceptible –Resistant Leishmania donovani, 10.1371/journal.pone.0026660
  12. Creek Darren J., Jankevics Andris, Breitling Rainer, Watson David G., Barrett Michael P., Burgess Karl E. V., Toward Global Metabolomics Analysis with Hydrophilic Interaction Liquid Chromatography–Mass Spectrometry: Improved Metabolite Identification by Retention Time Prediction, 10.1021/ac2021823
  13. De Gaudenzi Javier G., Noé Griselda, Campo Vanina A., Frasch Alberto C., Cassola Alejandro, Gene expression regulation in trypanosomatids, 10.1042/bse0510031
  14. Decuypere Saskia, Vanaerschot Manu, Brunker Kirstyn, Imamura Hideo, Müller Sylke, Khanal Basudha, Rijal Suman, Dujardin Jean-Claude, Coombs Graham H., Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background, 10.1371/journal.pntd.0001514
  15. DESCHACHT MAARTJE, VAN ASSCHE TIM, HENDRICKX SARAH, BULT HIDDE, MAES LOUIS, COS PAUL, Role of oxidative stress and apoptosis in the cellular response of murine macrophages upon Leishmania infection, 10.1017/s003118201200073x
  16. Downing T., Imamura H., Decuypere S., Clark T. G., Coombs G. H., Cotton J. A., Hilley J. D., de Doncker S., Maes I., Mottram J. C., Quail M. A., Rijal S., Sanders M., Schonian G., Stark O., Sundar S., Vanaerschot M., Hertz-Fowler C., Dujardin J.-C., Berriman M., Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance, 10.1101/gr.123430.111
  17. Dunn Warwick B, Broadhurst David, Begley Paul, Zelena Eva, Francis-McIntyre Sue, Anderson Nadine, Brown Marie, Knowles Joshau D, Halsall Antony, Haselden John N, Nicholls Andrew W, Wilson Ian D, Kell Douglas B, Goodacre Royston, Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry, 10.1038/nprot.2011.335
  18. El Fadili Karima, Drummelsmith Jolyne, Roy Gaétan, Jardim Armando, Ouellette Marc, Down regulation of KMP-11 in Leishmania infantum axenic antimony resistant amastigotes as revealed by a proteomic screen, 10.1016/j.exppara.2009.05.013
  19. Fahy E., Sud M., Cotter D., Subramaniam S., LIPID MAPS online tools for lipid research, 10.1093/nar/gkm324
  20. Hendrickx Sarah, Inocêncio da Luz Raquel Andrea, Bhandari Vasundhra, Kuypers Kristel, Shaw Craig D., Lonchamp Julien, Salotra Poonam, Carter Katharine, Sundar Shyam, Rijal Suman, Dujardin Jean-Claude, Cos Paul, Maes Louis, Experimental Induction of Paromomycin Resistance in Antimony-Resistant Strains of L. donovani: Outcome Dependent on In Vitro Selection Protocol, 10.1371/journal.pntd.0001664
  21. Jankevics Andris, Merlo Maria Elena, de Vries Marcel, Vonk Roel J., Takano Eriko, Breitling Rainer, Separating the wheat from the chaff: a prioritisation pipeline for the analysis of metabolomics datasets, 10.1007/s11306-011-0341-0
  22. Katajamaa Mikko, Orešič Matej, 10.1186/1471-2105-6-179
  23. Keller Bernd O., Sui Jie, Young Alex B., Whittal Randy M., Interferences and contaminants encountered in modern mass spectrometry, 10.1016/j.aca.2008.04.043
  24. Kompare Michelle, Rizzo William B., Mitochondrial Fatty-Acid Oxidation Disorders, 10.1016/j.spen.2008.05.008
  25. Principles of Fluorescence Spectroscopy, ISBN:9780387312781, 10.1007/978-0-387-46312-4
  26. Laurent Thierry, Rijal Suman, Yardley Vanessa, Croft Simon, De Doncker Simonne, Decuypere Saskia, Khanal Basudha, Singh Rupa, Schönian Gabriele, Kuhls Katrin, Epidemiological dynamics of antimonial resistance in Leishmania donovani: Genotyping reveals a polyclonal population structure among naturally-resistant clinical isolates from Nepal, 10.1016/j.meegid.2006.08.005
  27. Mottram Jeremy C., Robertson Colin D., Coombs Graham H., Barry J. David, A developmentally regulated cysteine proteinase gene of Leishmania mexicana, 10.1111/j.1365-2958.1992.tb01365.x
  28. Mukhopadhyay Rupkatha, Mukherjee Sandip, Mukherjee Budhaditya, Naskar Kshudiram, Mondal Dinesh, Decuypere Saskia, Ostyn Bart, Prajapati Vijay Kumar, Sundar Shyam, Dujardin Jean Claude, Roy Syamal, Characterisation of antimony-resistant Leishmania donovani isolates: Biochemical and biophysical studies and interaction with host cells, 10.1016/j.ijpara.2011.07.013
  29. Ogata H., Goto S., Sato K., Fujibuchi W., Bono H., Kanehisa M., KEGG: Kyoto Encyclopedia of Genes and Genomes, 10.1093/nar/27.1.29
  30. Opperdoes, Leishmania After the Genome, 123 (2008)
  31. OUAKAD M., VANAERSCHOT M., RIJAL S., SUNDAR S., SPEYBROECK N., KESTENS L., BOEL L., DE DONCKER S., MAES I., DECUYPERE S., DUJARDIN J.-C., Increased metacyclogenesis of antimony-resistant Leishmania donovani clinical lines, 10.1017/s0031182011001120
  32. Prince John T., Marcotte Edward M., Chromatographic Alignment of ESI-LC-MS Proteomics Data Sets by Ordered Bijective Interpolated Warping, 10.1021/ac0605344
  33. Requena Jose, M., Lights and shadows on gene organization and regulation of gene expression in Leishmania, 10.2741/3840
  34. Rijal Suman, Yardley Vanessa, Chappuis François, Decuypere Saskia, Khanal Basudha, Singh Rupa, Boelaert Marleen, De Doncker Simonne, Croft Simon, Dujardin Jean-Claude, Antimonial treatment of visceral leishmaniasis: are current in vitro susceptibility assays adequate for prognosis of in vivo therapy outcome?, 10.1016/j.micinf.2007.01.009
  35. Rosenzweig D., Smith D., Opperdoes F., Stern S., Olafson R. W., Zilberstein D., Retooling Leishmania metabolism: from sand fly gut to human macrophage, 10.1096/fj.07-9254com
  36. SAUNDERS ELEANOR C., DE SOUZA DAVID P., NADERER THOMAS, SERNEE MARIJKE F., RALTON JULIE E., DOYLE MARIA A., MACRAE JAMES I., CHAMBERS JENNY L., HENG JOANNE, NAHID AMSHA, LIKIC VLADIMIR A., MCCONVILLE MALCOLM J., Central carbon metabolism of Leishmania parasites, 10.1017/s0031182010000077
  37. Scalbert Augustin, Brennan Lorraine, Fiehn Oliver, Hankemeier Thomas, Kristal Bruce S., van Ommen Ben, Pujos-Guillot Estelle, Verheij Elwin, Wishart David, Wopereis Suzan, Mass-spectrometry-based metabolomics: limitations and recommendations for future progress with particular focus on nutrition research, 10.1007/s11306-009-0168-0
  38. Scheltema RA, Decuypere S, Dujardin JC, Watson DG, Jansen RC, Breitling R, Simple data-reduction method for high-resolution LC–MS data in metabolomics, 10.4155/bio.09.146
  39. Scheltema Richard A., Jankevics Andris, Jansen Ritsert C., Swertz Morris A., Breitling Rainer, PeakML/mzMatch: A File Format, Java Library, R Library, and Tool-Chain for Mass Spectrometry Data Analysis, 10.1021/ac2000994
  40. Shinitzky M., Inbar M., Difference in microviscosity induced by different cholesterol levels in the surface membrane lipid layer of normal lymphocytes and malignant lymphoma cells, 10.1016/0022-2836(74)90318-0
  41. Silva Ana Marta, Cordeiro-da-Silva Anabela, Coombs Graham H., Metabolic Variation during Development in Culture of Leishmania donovani Promastigotes, 10.1371/journal.pntd.0001451
  42. t’Kindt Ruben, Jankevics Andris, Scheltema Richard A., Zheng Liang, Watson David G., Dujardin Jean-Claude, Breitling Rainer, Coombs Graham H., Decuypere Saskia, Towards an unbiased metabolic profiling of protozoan parasites: optimisation of a Leishmania sampling protocol for HILIC-orbitrap analysis, 10.1007/s00216-010-4139-0
  43. t'Kindt Ruben, Scheltema Richard A., Jankevics Andris, Brunker Kirstyn, Rijal Suman, Dujardin Jean-Claude, Breitling Rainer, Watson David G., Coombs Graham H., Decuypere Saskia, Metabolomics to Unveil and Understand Phenotypic Diversity between Pathogen Populations, 10.1371/journal.pntd.0000904
  44. Tautenhahn Ralf, Bottcher Christoph, Neumann Steffen, Highly sensitive feature detection for high resolution LC/MS, 10.1186/1471-2105-9-504
  45. Vanaerschot Manu, Maes Ilse, Ouakad Meriem, Adaui Vanessa, Maes Louis, De Doncker Simonne, Rijal Suman, Chappuis François, Dujardin Jean-Claude, Decuypere Saskia, Linking In Vitro and In Vivo Survival of Clinical Leishmania donovani Strains, 10.1371/journal.pone.0012211
  46. Vanaerschot Manu, De Doncker Simonne, Rijal Suman, Maes Louis, Dujardin Jean-Claude, Decuypere Saskia, Antimonial Resistance in Leishmania donovani Is Associated with Increased In Vivo Parasite Burden, 10.1371/journal.pone.0023120
  47. Vanaerschot Manu, Decuypere Saskia, Berg Maya, Roy Syamal, Dujardin Jean-Claude, Drug-resistant microorganisms with a higher fitness – can medicines boost pathogens?, 10.3109/1040841x.2012.716818
  48. Vega Nicole M, Allison Kyle R, Khalil Ahmad S, Collins James J, Signaling-mediated bacterial persister formation, 10.1038/nchembio.915
  49. Vincent Isabel M., Creek Darren, Watson David G., Kamleh Mohammed A., Woods Debra J., Wong Pui Ee, Burchmore Richard J. S., Barrett Michael P., A Molecular Mechanism for Eflornithine Resistance in African Trypanosomes, 10.1371/journal.ppat.1001204
  50. Vincent Isabel M., Creek Darren J., Burgess Karl, Woods Debra J., Burchmore Richard J. S., Barrett Michael P., Untargeted Metabolomics Reveals a Lack Of Synergy between Nifurtimox and Eflornithine against Trypanosoma brucei, 10.1371/journal.pntd.0001618
  51. Walker John, Gongora Rafael, Vasquez Juan-José, Drummelsmith Jolyne, Burchmore Richard, Roy Gaetan, Ouellette Marc, Gomez Maria Adelaida, Saravia Nancy G., Discovery of factors linked to antimony resistance in Leishmania panamensis through differential proteome analysis, 10.1016/j.molbiopara.2012.03.002
  52. Wishart D. S., Tzur D., Knox C., Eisner R., Guo A. C., Young N., Cheng D., Jewell K., Arndt D., Sawhney S., Fung C., Nikolai L., Lewis M., Coutouly M.-A., Forsythe I., Tang P., Shrivastava S., Jeroncic K., Stothard P., Amegbey G., Block D., Hau David. D., Wagner J., Miniaci J., Clements M., Gebremedhin M., Guo N., Zhang Y., Duggan G. E., MacInnis G. D., Weljie A. M., Dowlatabadi R., Bamforth F., Clive D., Greiner R., Li L., Marrie T., Sykes B. D., Vogel H. J., Querengesser L., HMDB: the Human Metabolome Database, 10.1093/nar/gkl923
  53. Wyllie Susan, Cunningham Mark L., Fairlamb Alan H., Dual Action of Antimonial Drugs on Thiol Redox Metabolism in the Human PathogenLeishmania donovani, 10.1074/jbc.m405635200
  54. Zhang Kai, Beverley Stephen M., Phospholipid and sphingolipid metabolism in Leishmania, 10.1016/j.molbiopara.2009.12.004
  55. Zhang Ou, Xu Wei, Balakrishna Pillai Agiesh, Zhang Kai, Developmentally Regulated Sphingolipid Degradation in Leishmania major, 10.1371/journal.pone.0031059
Bibliographic reference Berg, Maya ; Vanaerschot, Manu ; Jankevics, Andris ; Cuypers, Bart ; Maes, Ilse ; et. al. Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure.. In: Molecular Microbiology, Vol. 90, no. 2, p. 428-442
Permanent URL http://hdl.handle.net/2078.1/134168