The Concept of Fitness in Leishmania

  • Manu Vanaerschot
  • Franck Dumetz
  • Marlene Jara
  • Jean-Claude Dujardin
  • Alicia Ponte-Sucre


A pathogen’s fitness relates to all biological processes that ensure its survival, reproduction, and transmission in specific conditions. These often include the presence of drugs, forcing pathogens to adapt and develop drug resistance in order to survive. The acquisition of a drug-resistant trait usually comes at a cost, making drug-resistant parasites less fit than their wild-type counterparts. This has important implications on the development of drug resistance and on the frequency of treatment failure cases in endemic regions. Treatment failure in patients suffering from leishmaniasis has been observed for most antileishmanials, but could not always be correlated to drug resistance of the infecting parasite. One similitude of both pentavalent antimonial and miltefosine treatment failure, however, relates to changes in parasite fitness. In the specific case of Leishmania donovani, for example, this may contrast with the usual fitness cost observed in natural drug-resistant organisms and highlights parasite fitness as an important contributor to treatment failure in visceral leishmaniasis in the Indian subcontinent. In this final chapter, we will canvass the knowns and the unknowns of Leishmania fitness at different parasite life stages and for different Leishmania species and discuss its relevance for the development and spread of drug resistance and/or treatment failure in the field. We will also propose new research avenues for leishmaniasis drug development and control in the context of current elimination efforts.


Fitness determinants Drug resistance Virulence Leishmaniasis Parasite fitness Fitness cost 


  1. 1.
    Bates M, Wrin T, Huang W, Petropoulos C, et al. Practical applications of viral fitness in clinical practice. Curr Opin Infect Dis. 2003;16:11–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Geretti AM. The clinical significance of viral fitness. J HIV Ther. 2005;10:6–10.PubMedGoogle Scholar
  3. 3.
    Quiñones-Mateu ME, Arts EJ. Virus fitness: concept, quantification, and application to HIV population dynamics. Curr Top Microbiol Immunol. 2006;299:83–140.PubMedGoogle Scholar
  4. 4.
    Andino R, Domingo E. Viral quasispecies. Virology. 2015;479–480:46–51.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Natera S, Machuca C, Padrón-Nieves M, Romero A, et al. Leishmania spp.: proficiency of drug-resistant parasites. Int J Antimicrob Agents. 2007;29:637–42.PubMedCrossRefGoogle Scholar
  6. 6.
    Vanaerschot M, Decuypere S, Berg M, Roy S, et al. Drug-resistant microorganisms with a higher fitness – can medicines boost pathogens? Crit Rev. Microbiol. 2012;39:1–11.Google Scholar
  7. 7.
    Semenza JC, Rocklöv J, Penttinen P, Lindgren E. Observed and projected drivers of emerging infectious diseases in Europe. Ann N Y Acad Sci. 2016;1382:73–83.PubMedCrossRefGoogle Scholar
  8. 8.
    Debrabant A, Nakhasi H. Programmed cell death in trypanosomatids: is it an altruistic mechanism for survival of the fittest? Kinetoplastid Biol Dis. 2003;2:7.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Gollob KJ, Viana AG, Dutra WO. Immunoregulation in human American leishmaniasis: balancing pathology and protection. Parasite Immunol. 2014;36:367–76.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Kima PE. The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist. Int J Parasitol. 2007;37:1087–96.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    El-Hani C, Borges VM, Wanderley JLM, Barcinski MA. Apoptosis and apoptotic mimicry in Leishmania: an evolutionary perspective. Front Cell Infect Microbiol. 2012;2:96.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bogdan C, Röllinghoff M. The immune response to Leishmania: mechanisms of parasite control and evasion. Int J Parasitol. 1998;28:121–34.PubMedCrossRefGoogle Scholar
  13. 13.
    Boggiatto PM, Jie F, Ghosh M, Gibson-Corley KN, et al. Altered dendritic cell phenotype in response to Leishmania amazonensis amastigote infection is mediated by MAP kinase, ERK. Am J Pathol. 2009;174:1818–26.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Xin L, Li K, Soong L. Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes. Mol Immunol. 2008;45:3371–82.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Van Assche T, Deschacht M, da Luz RAI, Maes L, et al. Leishmania–macrophage interactions: Insights into the redox biology. Free Radic Biol Med. 2011;51:337–51.PubMedCrossRefGoogle Scholar
  16. 16.
    Matte C, Descoteaux A. Leishmania donovani amastigotes impair gamma interferon-induced STAT1alpha nuclear translocation by blocking the interaction between STAT1alpha and importin-alpha5. Infect Immun. 2010;78:3736–43.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Abu-Dayyeh I, Hassani K, Westra ER, Mottram JC, et al. Comparative study of the ability of Leishmania mexicana promastigotes and amastigotes to alter macrophage signaling and functions. Infect Immun. 2010;78:2438–45.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Ruhland A, Kima PE. Activation of PI3K/Akt signaling has a dominant negative effect on IL-12 production by macrophages infected with Leishmania amazonensis promastigotes. Exp Parasitol. 2009;122:28–36.PubMedCrossRefGoogle Scholar
  19. 19.
    Rai AK, Thakur CP, Singh A, Seth T, et al. Regulatory T cells suppress T cell activation at the pathologic site of human visceral leishmaniasis. PLoS One. 2012;7:e31551.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Vanaerschot M, Dumetz F, Roy S, Ponte-Sucre A, et al. Treatment failure in leishmaniasis: drug-resistance or another (epi-) phenotype? Expert Rev Anti Infect Ther. 2014;12:937–46.PubMedCrossRefGoogle Scholar
  21. 21.
    Ghosh M, Roy K, Roy S. Immunomodulatory effects of antileishmanial drugs. J Antimicrob Chemother. 2013;68:2834–8.PubMedCrossRefGoogle Scholar
  22. 22.
    David Sibley L. Invasion and intracellular survival by protozoan parasites. Immunol Rev. 2011;240:72–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Guevara P, Rojas E, Gonzalez N, Scorza JV, et al. Presence of Leishmania braziliensis in blood samples from cured patients or at different stages of immunotherapy. Clin Diagn Lab Immunol. 1994;1:385–9.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Veland N, Espinosa D, Valencia BM, Ramos AP, et al. Polymerase chain reaction detection of Leishmania kDNA from the urine of Peruvian patients with cutaneous and mucocutaneous leishmaniasis. Am J Trop Med Hyg. 2011;84:556–61.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Figueroa RA, Lozano LE, Romero IC, Cardona MT, et al. Detection of Leishmania in unaffected mucosal tissues of patients with cutaneous leishmaniasis caused by Leishmania (Viannia) species. J Infect Dis. 2009;200:638–46.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Prina E, Roux E, Mattei D, Milon G. Leishmania DNA is rapidly degraded following parasite death: an analysis by microscopy and real-time PCR. Microbes Infect. 2007;9:1307–15.PubMedCrossRefGoogle Scholar
  27. 27.
    Deborggraeve S, Boelaert M, Rijal S, De Doncker S, et al. Diagnostic accuracy of a new Leishmania PCR for clinical visceral leishmaniasis in Nepal and its role in diagnosis of disease. Trop Med Int Heal. 2008;13:1378–83.CrossRefGoogle Scholar
  28. 28.
    Mukhopadhyay D, Dalton JE, Kaye PM, Chatterjee M. Post kala-azar dermal leishmaniasis: an unresolved mystery. Trends Parasitol. 2014;30:65–74.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Bogdan C, Donhauser N, Döring R, Röllinghoff M, et al. Fibroblasts as host cells in latent leishmaniosis. J Exp Med. 2000;191:2121–30.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Kloehn J, Saunders EC, O’Callaghan S, Dagley MJ, et al. Characterization of metabolically quiescent Leishmania parasites in murine lesions using heavy water labeling. PLOS Pathog. 2015;11:e1004683.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Alcolea PJ, Alonso A, Gómez MJ, Moreno I, et al. Transcriptomics throughout the life cycle of Leishmania infantum: High down-regulation rate in the amastigote stage. Int J Parasitol. 2010;40:1497–516.PubMedCrossRefGoogle Scholar
  32. 32.
    Michel G, Ferrua B, Lang T, Maddugoda MP, et al. Luciferase-expressing Leishmania infantum allows the monitoring of amastigote population size, in vivo, ex vivo and in vitro. PLoS Negl Trop Dis. 2011;5:e1323.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Biyani N, Madhubala R. Quantitative proteomic profiling of the promastigotes and the intracellular amastigotes of Leishmania donovani isolates identifies novel proteins having a role in Leishmania differentiation and intracellular survival. Biochim Biophys Acta. 2012;1824:1342–50.PubMedCrossRefGoogle Scholar
  34. 34.
    Cloutier S, Laverdière M, Chou M-N, Boilard N, et al. (2012) Translational control through eIF2alpha phosphorylation during the Leishmania differentiation process. PLoS One 7:e35085.Google Scholar
  35. 35.
    Saunders EC, Ng WW, Kloehn J, Chambers JM, et al. Induction of a stringent metabolic response in intracellular stages of Leishmania mexicana leads to increased dependence on mitochondrial metabolism. PLoS Pathog. 2014;10:e1003888.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Mondal S, Roy JJ, Bera T. Characterization of mitochondrial bioenergetic functions between two forms of Leishmania donovani – a comparative analysis. J Bioenerg Biomembr. 2014;46:395–402.PubMedCrossRefGoogle Scholar
  37. 37.
    Mandell MA, Beverley SM. Continual renewal and replication of persistent Leishmania major parasites in concomitantly immune hosts. Proc Natl Acad Sci USA. 2017;114:E801–10.PubMedCrossRefGoogle Scholar
  38. 38.
    Dillon RJ, Ivens AC, Churcher C, Holroyd N, et al. Analysis of ESTs from Lutzomyia longipalpis sand flies and their contribution toward understanding the insect-parasite relationship. Genomics. 2006;88:831–40.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Diaz E, Zacarias AK, Pérez S, Vanegas O, et al. Effect of aliphatic, monocarboxylic, dicarboxylic, heterocyclic and sulphur-containing amino acids on Leishmania spp. chemotaxis. Parasitology. 2015;142:1621–30.PubMedCrossRefGoogle Scholar
  40. 40.
    Schlein Y, Jacobson RL, Shlomai J. Chitinase secreted by Leishmania functions in the sandfly vector. Proceedings Biol Sci. 1991;245:121–6.CrossRefGoogle Scholar
  41. 41.
    Sacks DL, Melby PC. Animal models for the analysis of immune responses to leishmaniasis. Curr Protoc Immunol. 2001.
  42. 42.
    da Silva R, Sacks DL. Metacyclogenesis is a major determinant of Leishmania promastigote virulence and attenuation. Infect Immun. 1987;55:2802–6.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Rogers ME, Chance ML, Bates PA. The role of promastigote secretory gel in the origin and transmission of the infective stage of Leishmania mexicana by the sandfly Lutzomyia longipalpis. Parasitology. 2002;124:495–507.PubMedCrossRefGoogle Scholar
  44. 44.
    Bates PA. Transmission of Leishmania metacyclic promastigotes by phlebotomine sand flies. Int J Parasitol. 2007;37:1097–106.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Aslan H, Dey R, Meneses C, Castrovinci P, et al. A new model of progressive visceral leishmaniasis in hamsters by natural transmission via bites of vector sand flies. J Infect Dis. 2013;207:1328–38.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Barrett MP, Burchmore RJ, Stich A, Lazzari JO, et al. The trypanosomiases. Lancet. 2003;362:1469–80.PubMedCrossRefGoogle Scholar
  47. 47.
    Sunkin SM, Kiser P, Myler PJ, Stuart K. The size difference between Leishmania major friedlin chromosome one homologues is localized to sub-telomeric repeats at one chromosomal end. Mol Biochem Parasitol. 2000;109:1–15.PubMedCrossRefGoogle Scholar
  48. 48.
    Johnson PJ, Kooter JM, Borst P. Inactivation of transcription by UV irradiation of T. brucei provides evidence for a multicistronic transcription unit including a VSG gene. Cell. 1987;51:273–81.PubMedCrossRefGoogle Scholar
  49. 49.
    Fairlamb AH, Blackburn P, Ulrich P, Chait BT, et al. Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids. Science. 1985;227:1485–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Mukhopadhyay R, Dey S, Xu N, Gage D, et al. Trypanothione overproduction and resistance to antimonials and arsenicals in Leishmania. Proc Natl Acad Sci U S A. 1996;93:10383–7.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Krauth-Siegel RL, Meiering SK, Schmidt H. The Parasite-Specific Trypanothione Metabolism of Trypanosoma and Leishmania. Biol Chem. 2003;384:539–49.PubMedCrossRefGoogle Scholar
  52. 52.
    Sterkers Y, Lachaud L, Crobu L, Bastien P, et al. FISH analysis reveals aneuploidy and continual generation of chromosomal mosaicism in Leishmania major. Cell Microbiol. 2011;13:274–83.PubMedCrossRefGoogle Scholar
  53. 53.
    Sterkers Y, Lachaud L, Bourgeois N, Crobu L, et al. Novel insights into genome plasticity in Eukaryotes: mosaic aneuploidy in Leishmania. Mol Microbiol. 2012;86:15–23.PubMedCrossRefGoogle Scholar
  54. 54.
    Lachaud L, Bourgeois N, Kuk N, Morelle C, et al. Constitutive mosaic aneuploidy is a unique genetic feature widespread in the Leishmania genus. Microbes Infect. 2013:2–7.Google Scholar
  55. 55.
    Prieto-Barja P, Pesher P, Bussotti G, Dumetz F, et al. Haplotype selection as an adaptive mechanism in the protozoan pathogen Leishmania donovani. Nat Ecol Evol. 2017;1:1961–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Leprohon P, Légaré D, Raymond F, Madore E, et al. Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum. Nucleic Acids Res. 2009;37:1387–99.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Shaw CD, Lonchamp J, Downing T, Imamura H, et al. In vitro selection of miltefosine resistance in promastigotes of Leishmania donovani from Nepal: genomic and metabolomic characterization. Mol Microbiol. 2016;99:1134–48.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Ubeda J-M, Raymond F, Mukherjee A, Plourde M, et al. Genome-wide stochastic adaptive DNA amplification at direct and inverted DNA repeats in the parasite Leishmania. PLoS Biol. 2014;12:e1001868.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Imamura H, Downing T, Van den Broeck F, Sanders MJ, et al. Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent. Elife. 2016;5:1–39.CrossRefGoogle Scholar
  60. 60.
    Monte-Neto R, Laffitte M-CN, Leprohon P, Reis P, et al. Intrachromosomal amplification, locus deletion and point mutation in the aquaglyceroporin AQP1 gene in antimony resistant Leishmania (Viannia) guyanensis. PLoS Negl Trop Dis. 2015;9:e0003476.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Grondin K, Papadopoulou B, Ouellette M. Homologous recombination between direct repeat sequences yields P-glycoprotein containing amplicons in arsenite resistant Leishmania. Nucleic Acids Res. 1993;21:1895–901.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Moreira DS, Monte Neto RL, Andrade JM, Santi AMM, et al. Molecular characterization of the MRPA transporter and antimony uptake in four New World Leishmania spp. susceptible and resistant to antimony. Int J Parasitol Drugs Drug Resist. 2013;3:143–53.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Brotherton M-C, Bourassa S, Leprohon P, Légaré D, et al. Proteomic and genomic analyses of antimony resistant Leishmania infantum mutant. PLoS One. 2013;8:e81899.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Singh A, Papadopoulou B, Ouellette M. Gene amplification in amphotericin B-resistant Leishmania tarentolae. Exp Parasitol. 2001;99:141–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Papadopoulou B, Roy G, Ouellette M. Frequent amplification of a short chain dehydrogenase gene as part of circular and linear amplicons in methotrexate resistant Leishmania. Nucleic Acids Res. 1993;21:4305–12.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Grondin K, Roy G, Ouellette M. Formation of extrachromosomal circular amplicons with direct or inverted duplications in drug-resistant Leishmania tarentolae. Mol Cell Biol. 1996;16:3587–95.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Ubeda J-M, Légaré D, Raymond F, Ouameur AA, et al. Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy. Genome Biol. 2008;9:R115.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Ritt J-F, Raymond F, Leprohon P, Légaré D, et al. Gene amplification and point mutations in pyrimidine metabolic genes in 5-fluorouracil resistant Leishmania infantum. PLoS Negl Trop Dis. 2013;7:e2564.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Kumar P, Lodge R, Raymond F, Ritt J-F, et al. Gene expression modulation and the molecular mechanisms involved in Nelfinavir resistance in Leishmania donovani axenic amastigotes. Mol Microbiol. 2013:1–18.Google Scholar
  70. 70.
    Berg M, Vanaerschot M, Jankevics A, Cuypers B, et al. Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure. Mol Microbiol. 2013;90:428–42.PubMedGoogle Scholar
  71. 71.
    Ariyanayagam MR, Fairlamb AH. Ovothiol and trypanothione as antioxidants in trypanosomatids. Mol Biochem Parasitol. 2001;115:189–98.PubMedCrossRefGoogle Scholar
  72. 72.
    Bocedi A, Dawood KF, Fabrini R, Federici G, et al. (2010) Trypanothione efficiently intercepts nitric oxide as a harmless iron complex in trypanosomatid parasites. FASEB J 24:1035–1042.Google Scholar
  73. 73.
    Romão PRT, Tovar J, Fonseca SG, Moraes RH, et al. Glutathione and the redox control system trypanothione/trypanothione reductase are involved in the protection of Leishmania spp. against nitrosothiol-induced cytotoxicity. Brazilian J Med Biol Res Rev. 2006;39:355–63.CrossRefGoogle Scholar
  74. 74.
    Piñeyro MD, Arcari T, Robello C, Radi R, et al. Tryparedoxin peroxidases from Trypanosoma cruzi: High efficiency in the catalytic elimination of hydrogen peroxide and peroxynitrite. Arch Biochem Biophys. 2011;507:287–95.PubMedCrossRefGoogle Scholar
  75. 75.
    Flohé L, Budde H, Bruns K, Castro H, et al. Tryparedoxin peroxidase of Leishmania donovani: molecular cloning, heterologous expression, specificity, and catalytic mechanism. Arch Biochem Biophys. 2002;397:324–35.PubMedCrossRefGoogle Scholar
  76. 76.
    Alvarez MN, Peluffo G, Piacenza L, Radi R. Intraphagosomal peroxynitrite as a macrophage-derived cytotoxin against internalized Trypanosoma cruzi: consequences for oxidative killing and role of microbial peroxiredoxins in infectivity. J Biol Chem. 2011;286:6627–40.PubMedCrossRefGoogle Scholar
  77. 77.
    Iyer JP, Kaprakkaden A, Choudhary ML, Shaha C. Crucial role of cytosolic tryparedoxin peroxidase in Leishmania donovani survival, drug response and virulence. Mol Microbiol. 2008;68:372–91.PubMedCrossRefGoogle Scholar
  78. 78.
    Dumas C, Ouellette M, Tovar J, Cunningham ML, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Tovar J, Wilkinson S, Mottram JC, Fairlamb AH. Evidence that trypanothione reductase is an essential enzyme in Leishmania by targeted replacement of the tryA gene locus. Mol Microbiol. 1998;29:653–60.PubMedCrossRefGoogle Scholar
  80. 80.
    Tovar J, Cunningham ML, Smith AC, Croft SL, et al. Down-regulation of Leishmania donovani trypanothione reductase by heterologous expression of a trans-dominant mutant homologue: effect on parasite intracellular survival. Proc Natl Acad Sci USA. 1998;95:5311–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Rojo D, Canuto GAB, Castilho-Martins EA, Tavares MFM, et al. A multiplatform metabolomic approach to the basis of antimonial action and resistance in Leishmania infantum. PLoS One. 2015;10:1–20.CrossRefGoogle Scholar
  82. 82.
    Berg M, Garcia-Hernandez R, Cuypers B, Vanaerschot M, et al. Experimental resistance to drug combinations in Leishmania donovani: Metabolic and phenotypic adaptations. Antimicrob Agents Chemother. 2015;59:2242–55.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Decuypere S, Rijal S, Yardley V, De Doncker S, et al. Gene expression analysis of the mechanism of natural Sb(V) resistance in Leishmania donovani isolates from Nepal. Antimicrob Agents Chemother. 2005;49:4616–21.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Decuypere S, Vanaerschot M, Brunker K, Imamura H, et al. Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background. PLoS Negl Trop Dis. 2012;6:e1514.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Gómez Pérez V, García-Hernandez R, Corpas-López V, Tomás AM, et al. Decreased antimony uptake and overexpression of genes of thiol metabolism are associated with drug resistance in a canine isolate of Leishmania infantum. Int J Parasitol Drugs Drug Resist. 2016;6:133–9.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Canuto GAB, Castilho-Martins EA, Tavares MFM, Rivas L, et al. Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania. Anal Bioanal Chem. 2014;406:3459–76.PubMedCrossRefGoogle Scholar
  87. 87.
    t’Kindt R, R a S, Jankevics A, Brunker K, et al. Metabolomics to unveil and understand phenotypic diversity between pathogen populations. PLoS Negl Trop Dis. 2010;e904:4.Google Scholar
  88. 88.
    Oryan A, Shirian S, Tabandeh M-R, Hatam G-R, et al. Genetic diversity of Leishmania major strains isolated from different clinical forms of cutaneous leishmaniasis in southern Iran based on minicircle kDNA. Infect Genet Evol. 2013;19:226–31.PubMedCrossRefGoogle Scholar
  89. 89.
    CoreWriting Team, Pachauri RK. Climate Change 2014: Synthesis report contributions of working groups I, II and III to the fifth assessment report of the IPCC. 2014.Google Scholar
  90. 90.
    Brunner FS, Eizaguirre C. Can environmental change affect host/parasite-mediated speciation? Zoology. 2016;119:384–94.PubMedCrossRefGoogle Scholar
  91. 91.
    Thomas CD, Cameron A, Green RE, Bakkenes M, et al. Extinction risk from climate change. Nature. 2004;427:145–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Kutz SJ, Hoberg EP, Polley L, Jenkins EJ. Global warming is changing the dynamics of Arctic host-parasite systems. Proc Biol Sci. 2005;272:2571–6.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Larsen MH, Mouritsen KN. Temperature–parasitism synergy alters intertidal soft-bottom community structure. J Exp Mar Bio Ecol. 2014;460:109–19.CrossRefGoogle Scholar
  94. 94.
    Mitchell SE, Rogers ES, Little TJ, Read AF. Host-parasite and genotype-by-environment interactions: temperature modifies potential for selection by a sterilizing pathogen. Evolution. 2005;59:70–80.PubMedCrossRefGoogle Scholar
  95. 95.
    Macnab V, Barber I. Some (worms) like it hot: fish parasites grow faster in warmer water, and alter host thermal preferences. Glob Chang Biol. 2012;18:1540–8.CrossRefGoogle Scholar
  96. 96.
    Scharsack JP, Schweyen H, Schmidt AM, Dittmar J, et al. Population genetic dynamics of three-spined sticklebacks (Gasterosteus aculeatus) in anthropogenic altered habitats. Ecol Evol. 2012;2:1122–43.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Jiménez M, Alvar J, Tibayrenc M. Leishmania infantum is clonal in AIDS patients too: epidemiological implications. AIDS. 1997;11:569–73.PubMedCrossRefGoogle Scholar
  98. 98.
    Rosenthal E, Marty P, Poizot-Martin I, Reynes J, et al. Visceral leishmaniasis and HIV-1 co-infection in southern France. Trans R Soc Trop Med Hyg. 1995;89:159–62.PubMedCrossRefGoogle Scholar
  99. 99.
    Lopez-Velez R, Perez-Molina JA, Guerrero A, Baquero F, et al. Clinico epidemiologic characteristics, prognostic factors, and survival analysis of patients coinfected with human immunodeficiency virus and Leishmania in an area of Madrid, Spain. Am J Trop Med Hyg. 1998;58:436–43.PubMedCrossRefGoogle Scholar
  100. 100.
    Bryceson AD, Chulay JD, Ho M, Mugambii M, et al. Visceral leishmaniasis unresponsive to antimonial drugs. I. Clinical and immunological studies. Trans R Soc Trop Med Hyg. 1985;79:700–4.PubMedCrossRefGoogle Scholar
  101. 101.
    Davidson RN, Di Martino L, Gradoni L, Giacchino R, et al. Liposomal amphotericin B (AmBisome) in Mediterranean visceral leishmaniasis: a multi-centre trial. Q J Med. 1994;87:75–81.PubMedGoogle Scholar
  102. 102.
    Bryceson A. Current issues in the treatment of visceral leishmaniasis. Med Microbiol Immunol. 2001;190:81–4.PubMedCrossRefGoogle Scholar
  103. 103.
    Ives A, Ronet C, Prevel F, Ruzzante G, Fuertes-Marraco S, et al. Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis. Science. 2011;331(6018):775–8.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Cantanhêde LM, da Silva Júnior CF, Ito MM, Felipin KP, et al. Further evidence of an association between the presence of Leishmania RNA virus 1 and the mucosal manifestations in tegumentary leishmaniasis patients. PLoS Negl Trop Dis. 2015;9:e0004079.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Adaui V, Lye L-F, Akopyants NS, Zimic M, et al. Association of the endobiont double-stranded RNA virus LRV1 with treatment failure for human leishmaniasis caused by Leishmania braziliensis in Peru and Bolivia. J Infect Dis. 2016;213:112–21.PubMedCrossRefGoogle Scholar
  106. 106.
    Arevalo J, Ramirez L, Adaui V, Zimic M, et al. Influence of Leishmania (Viannia) species on the response to antimonial treatment in patients with American tegumentary leishmaniasis. J Infect Dis. 2007;195:1846–51.PubMedCrossRefGoogle Scholar
  107. 107.
    Romero GA, Guerra MV, Paes MG, Macêdo VO. Comparison of cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis and L. (V.) guyanensis in Brazil: therapeutic response to meglumine antimoniate. Am J Trop Med Hyg. 2001;65:456–65.PubMedCrossRefGoogle Scholar
  108. 108.
    Zerpa O, Convit J. Diffuse cutaneous leishmaniasis in Venezuela. Gaz méd Bahia. 2009;79:30–4.Google Scholar
  109. 109.
    Goto H, Lindoso JAL. Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther. 2010;8:419–33.PubMedCrossRefGoogle Scholar
  110. 110.
    Ponte-Sucre A, Diaz E, Padrón-Nieves M. The concept of fitness and drug resistance in Leishmania. In: Ponte-Sucre A, Diaz E, Padrón-Nieves M, editors. Drug Resist. Leishmania parasites, Consequences, molecular mechanisms and possible treatments. Vienna: Springer; 2013. p. 431–49.CrossRefGoogle Scholar
  111. 111.
    Newton PN, Green MD, Fernández FM. Impact of poor-quality medicines in the “developing” world. Trends Pharmacol Sci. 2010;31:99–101.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    de Mello CX, de Oliveira Schubach A, de Oliveira RVC, Conceição-Silva F, et al. Comparison of the sensitivity of imprint and scraping techniques in the diagnosis of American tegumentary leishmaniasis in a referral centre in Rio de Janeiro, Brazil. Parasitol Res. 2011;109:927–33.PubMedCrossRefGoogle Scholar
  113. 113.
    Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol. 2010;8:260–71.PubMedCrossRefGoogle Scholar
  114. 114.
    Melnyk AH, Wong A, Kassen R. The fitness costs of antibiotic resistance mutations. Evol Appl. 2015;8:273–83.PubMedCrossRefGoogle Scholar
  115. 115.
    Huijben S, Bell AS, Sim DG, Tomasello D, et al. Aggressive chemotherapy and the selection of drug resistant pathogens. PLoS Pathog. 2013;9:e1003578.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Ouakad M, Vanaerschot M, Rijal S, Sundar S, et al. Increased metacyclogenesis of antimony-resistant Leishmania donovani clinical lines. Parasitology. 2011;138:1392–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Vanaerschot M, Maes I, Ouakad M, Adaui V, et al. Linking in vitro and in vivo survival of clinical Leishmania donovani strains. PLoS One. 2010;5:e12211.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Vanaerschot M, de Doncker S, Rijal S, Maes L, et al. Antimonial resistance in Leishmania donovani is associated with increased in vivo parasite burden. PLoS One. 2011;6:e23120.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Imamura H, Downing T, Van den Broeck F, Sanders MJ, et al. Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent. Elife. 2016;5:e12613. Scholar
  120. 120.
    Stauch A, Sarkar RR, Picado A, Ostyn B, et al. Visceral leishmaniasis in the Indian subcontinent: modelling epidemiology and control. PLoS Negl Trop Dis. 2011;5:e1405.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Stauch A, Duerr HP, Dujardin JC, Vanaerschot M, et al. Treatment of visceral leishmaniasis: model-based analyses on the spread of antimony-resistant L. donovani in Bihar, India. PLoS Negl Trop Dis. 2012;6(12):e1973.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Rai K, Bhattarai NR, Vanaerschot M, Imamura H, et al. Single locus genotyping to track Leishmania donovani in the Indian subcontinent: Application in Nepal. PLoS Negl Trop Dis. 2017;11:e0005420.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Rai K, Cuypers B, Bhattarai NR, Uranw S, et al. Relapse after treatment with Miltefosine for visceral Leishmaniasis is associated with increased infectivity of the infecting Leishmania donovani strain. MBio. 2013;4:e00611-13.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    García-Hernández R, Gómez-Pérez V, Castanys S, Gamarro F. Fitness of Leishmania donovani parasites resistant to drug combinations. PLoS Negl Trop Dis. 2015;9:e0003704.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Hendrickx S, Beyers J, Mondelaers A, Eberhardt E, et al. Evidence of a drug-specific impact of experimentally selected paromomycin and miltefosine resistance on parasite fitness in Leishmania infantum. J Antimicrob Chemother. 2016;71:1914–21.PubMedCrossRefGoogle Scholar
  126. 126.
    Turner KG, Vacchina P, Robles-Murguia M, Wadsworth M, et al. Fitness and phenotypic characterization of Miltefosine-resistant Leishmania major. PLoS Negl Trop Dis. 2015;9:e0003948.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Padrón-Nieves M, Machuca C, Díaz E, Cotrim P, et al. Correlation between glucose uptake and membrane potential in Leishmania parasites isolated from DCL patients with therapeutic failure: a proof of concept. Parasitol Res. 2014;113:2121–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Ponte-Sucre A. Leishmaniasis, the biology of a parasite. In: Ponte-Sucre A, Padron Nieves M, editors. Drug Resist. Leishmania parasites, Consequences, molecular mechanisms and possible treatments. Vienna: Springer; 2013. p. 1–12.CrossRefGoogle Scholar
  129. 129.
    Padron-Nieves M, Ponte-Sucre A. Marcadores de resistencia en Leishmania: susceptibilidad in vitro a drogas leishmanicidas vs. retencion de calceina en aislados de pacientes venezolanos con leishmaniasis cutanea difusa. Arch Venez Farmacol y Ter. 2015;32:29–33.Google Scholar
  130. 130.
    Zerpa O, Ulrich M, Blanco B, Polegre M, et al. Diffuse cutaneous leishmaniasis responds to miltefosine but then relapses. Br J Dermatol. 2007;156:1328–35.PubMedCrossRefGoogle Scholar
  131. 131.
    Torrico MC, De Doncker S, Arevalo J, Le Ray D, et al. In vitro promastigote fitness of putative Leishmania (Viannia) braziliensis/Leishmania (Viannia) peruviana hybrids. Acta Trop. 1999;72:99–110.PubMedCrossRefGoogle Scholar
  132. 132.
    Hartley M-A, Ronet C, Zangger H, Beverley SM, et al. Leishmania RNA virus: when the host pays the toll. Front Cell Infect Microbiol. 2012;2:99.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Taylor DR, Jarosz AM, Fulbright DW, Lenski RE. The acquisition of hypovirulence in host-pathogen systems with three trophic levels. Am Nat. 1998;151:343–55.PubMedGoogle Scholar
  134. 134.
    Maisonneuve E, Gerdes K. Molecular mechanisms underlying bacterial persisters. Cell. 2014;157:539–48.PubMedCrossRefGoogle Scholar
  135. 135.
    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.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Callahan HL, Portal AC, Devereaux R, Grogl M. An axenic amastigote system for drug screening. Antimicrob Agents Chemother. 1997;41:818–22.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Kaur G, Rajput B. Comparative analysis of the omics technologies used to study antimonial, amphotericin B, and pentamidine resistance in Leishmania. J Parasitol Res. 2014;2014:1–11.CrossRefGoogle Scholar
  138. 138.
    Saravia NG, Weigle K, Segura I, Giannini SH, et al. Recurrent lesions in human Leishmania braziliensis infection--reactivation or reinfection? Lancet (London, England). 1990;336:398–402.CrossRefGoogle Scholar
  139. 139.
    Nühs A, De Rycker M, Manthri S, Comer E, et al. Development and validation of a novel Leishmania donovani screening cascade for high-throughput screening using a novel axenic assay with high predictivity of leishmanicidal intracellular activity. PLoS Negl Trop Dis. 2015;9:e0004094.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Tegazzini D, Díaz R, Aguilar F, Peña I, et al. A replicative in vitro assay for drug discovery against Leishmania donovani. Antimicrob Agents Chemother. 2016;60:3524–32.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Hefnawy A, Berg M, Dujardin J-C, De Muylder G. Exploiting knowledge on Leishmania drug resistance to support the quest for new drugs. Trends Parasitol. 2017;33:162–74.PubMedCrossRefGoogle Scholar
  142. 142.
    Le Rutte EA, Coffeng LE, Bontje DM, Hasker EC, et al. Feasibility of eliminating visceral leishmaniasis from the Indian subcontinent: explorations with a set of deterministic age-structured transmission models. Parasit Vectors. 2016;9:24.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Gabryszewski SJ, Modchang C, Musset L, Chookajorn T, et al. Combinatorial genetic modeling of pfcrt -mediated drug resistance evolution in Plasmodium falciparum. Mol Biol Evol. 2016;33:1554–70.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Manu Vanaerschot
    • 1
  • Franck Dumetz
    • 2
  • Marlene Jara
    • 3
  • Jean-Claude Dujardin
    • 2
    • 4
  • Alicia Ponte-Sucre
    • 5
  1. 1.Department of Microbiology and ImmunologyColumbia University College of Physicians and SurgeonsNew YorkUSA
  2. 2.Department of Biomedical Sciences, Institute of Tropical MedicineAntwerpBelgium
  3. 3.Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano HerediaLimaPeru
  4. 4.Department of Biomedical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary SciencesUniversity of AntwerpAntwerpenBelgium
  5. 5.Laboratory of Molecular Physiology, Institute of Experimental Medicine, Luis Razetti School of Medicine, Faculty of Medicine, Universidad Central de Venezuela CaracasCaracasVenezuela

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