Parasitology

Research Article

Increased metacyclogenesis of antimony-resistant Leishmania donovani clinical lines

M. OUAKADa1, M. VANAERSCHOTa1a6, S. RIJALa2, S. SUNDARa3, N. SPEYBROECKa4, L. KESTENSa5, L. BOELa5, S. DE DONCKERa1, I. MAESa1, S. DECUYPEREa1 and J.-C. DUJARDINa1a6 c1

a1 Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium

a2 Department of Internal Medicine, B.P. Koirala Institute of Health Sciences, Dharan, Nepal

a3 Banaras Hindu University, Varanasi, India

a4 Institute of Health and Society, Université Catholique de Louvain, Belgium

a5 Unit of Immunology, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium

a6 Laboratory for Microbiology, Parasitology and Hygiene, Department of Biomedical Sciences, Antwerp University, Antwerp, Belgium

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.

(Received March 04 2011)

(Revised April 29 2011)

(Revised May 31 2011)

(Accepted June 01 2011)

(Online publication August 08 2011)

Correspondence:

c1 Corresponding author: Unit of Molecular Parasitology, Institute of Tropical Medicine, Antwerp, Nationalestraat, 155, B-2000 Belgium. Tel: 00 32 3 2476358. Fax: 00 32 3 2476359. E-mail: jcdujardin@itg.be

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