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Increased metacyclogenesis of antimony-resistant Leishmania donovani clinical lines

Published online by Cambridge University Press:  08 August 2011

M. OUAKAD ,
M. VANAERSCHOT ,
S. RIJAL ,
S. SUNDAR ,
N. SPEYBROECK ,
L. KESTENS ,
L. BOEL ,
S. DE DONCKER ,
I. MAES  and
S. DECUYPERE
...Show all authors
M. OUAKAD
Affiliation:
Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium
M. VANAERSCHOT
Affiliation:
Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium Laboratory for Microbiology, Parasitology and Hygiene, Department of Biomedical Sciences, Antwerp University, Antwerp, Belgium
S. RIJAL
Affiliation:
Department of Internal Medicine, B.P. Koirala Institute of Health Sciences, Dharan, Nepal
S. SUNDAR
Affiliation:
Banaras Hindu University, Varanasi, India
N. SPEYBROECK
Affiliation:
Institute of Health and Society, Université Catholique de Louvain, Belgium
L. KESTENS
Affiliation:
Unit of Immunology, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium
L. BOEL
Affiliation:
Unit of Immunology, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium
S. DE DONCKER
Affiliation:
Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium
I. MAES
Affiliation:
Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium
S. DECUYPERE
Affiliation:
Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium
J.-C. DUJARDIN*
Affiliation:
Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium Laboratory for Microbiology, Parasitology and Hygiene, Department of Biomedical Sciences, Antwerp University, Antwerp, Belgium
*
*Corresponding author: Unit of Molecular Parasitology, Institute of Tropical Medicine, Antwerp, Nationalestraat, 155, B-2000Belgium. Tel: 00 32 3 2476358. Fax: 00 32 3 2476359. E-mail: jcdujardin@itg.be
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Summary

Mathematical models predict that the future of epidemics of drug-resistant pathogens depends in part on the competitive fitness of drug-resistant strains. Considering metacyclogenesis (differentiation process essential for infectivity) as a major contributor to the fitness of Leishmania donovani, we tested its relationship with pentavalent antimony (SbV) resistance in clinical lines. Different methods for the assessment of metacyclogenesis were cross-validated: gene expression profiling (META1 and SHERP), morphometry (microscopy and FACS), in vitro infectivity to macrophages and resistance to complement lysis. This was done on a model constituted by 2 pairs of reference strains cloned from a SbV-resistant and -sensitive isolate. We selected the most adequate parameter and extended the analysis of metacyclogenesis diversity to a sample of 20 clinical lines with different in vitro susceptibility to the drug. The capacity of metacyclogenesis, as measured by the complement lysis test, was shown to be significantly higher in SbV-resistant clinical lines of L. donovani than in SbV-sensitive lines. Together with other lines of evidence, it is concluded that L. donovani constitutes a unique example and model of drug-resistant pathogens with traits of increased fitness. These findings raise a fundamental question about the potential risks of selecting more virulent pathogens through massive chemotherapeutic interventions.

Keywords

Leishmania donovanivisceral leishmaniasisNepalIndiaantimony resistancemetacyclogenesisSHERPMETA1
Type
Research Article
Information
Parasitology , Volume 138 , Issue 11 , September 2011 , pp. 1392 - 1399
Copyright
Copyright © Cambridge University Press 2011

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