1. Increased metacyclogenesis of antimony-resistant **Leishmania donovani** clinical lines
- Author
-
M Ouakad, Suman Rijal, Ilse Maes, J-C Dujardin, Shyam Sundar, Manu Vanaerschot, L Boel, Saskia Decuypere, L Kestens, S. De Doncker, and Niko Speybroeck
- Subjects
Antimony ,Resistance ,Drug Resistance ,Protozoan Proteins ,Strains ,Drug resistance ,0302 clinical medicine ,Leishmaniasis ,Infectivity ,Visceral ,0303 health sciences ,Diversity ,Drug susceptibility ,biology ,Protozoal diseases ,Vectors ,Flow Cytometry ,3. Good health ,Infectious Diseases ,Leishmaniasis, Visceral ,Kala azar ,030231 tropical medicine ,Antiprotozoal Agents ,Leishmania donovani ,Virulence ,Assessment ,Real-Time Polymerase Chain Reaction ,Microbiology ,03 medical and health sciences ,Sandflies ,In vitro ,medicine ,Animals ,Humans ,Life Cycle Stages ,030306 microbiology ,Gene Expression Profiling ,Morphometry ,Macrophages ,Modeling ,Laboratory techniques and procedures ,medicine.disease ,biology.organism_classification ,Molecular Typing ,Gene expression profiling ,Visceral leishmaniasis ,Antimony Sodium Gluconate ,Immunology ,Phlebotomus argentipes ,Animal Science and Zoology ,Parasitology ,Gene expression ,Human medicine ,Metacyclogenesis - Abstract
SUMMARYMathematical 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.
- Published
- 2011