title: Increased metacyclogenesis of antimony-resistant Leishmania donovani clinical lines.
abstract: 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.
authors.affiliation: Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Ouakad
authors.forename: M
authors.initials: M
authors.lastname: Vanaerschot
authors.forename: S
authors.initials: S
authors.lastname: Rijal
authors.forename: S
authors.initials: S
authors.lastname: Sundar
authors.forename: N
authors.initials: N
authors.lastname: Speybroeck
authors.forename: L
authors.initials: L
authors.lastname: Kestens
authors.forename: L
authors.initials: L
authors.lastname: Boel
authors.forename: S
authors.initials: S
authors.lastname: De Doncker
authors.forename: I
authors.initials: I
authors.lastname: Maes
authors.forename: S
authors.initials: S
authors.lastname: Decuypere
authors.forename: J-C
authors.initials: JC
authors.lastname: Dujardin
mesh_terms: D000818:Animals; D000967:Antimony Sodium Gluconate / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007893:Leishmania donovani / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008018:Life Cycle Stages / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000469:parasitology; D058889:Molecular Typing; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D000967:Antimony Sodium Gluconate