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Originally published In Press as doi:10.1074/mcp.M600319-MCP200 on October 17, 2006.
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Molecular & Cellular Proteomics 6:88-101, 2007.
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

A Proteomics Screen Implicates HSP83 and a Small Kinetoplastid Calpain-related Protein in Drug Resistance in Leishmania donovani Clinical Field Isolates by Modulating Drug-induced Programmed Cell Death*

Baptiste Vergnes{ddagger},§, Benjamin Gourbal{ddagger},¶, Isabelle Girard{ddagger}, Shyam Sundar||, Jolyne Drummelsmith{ddagger},** and Marc Ouellette{ddagger},{ddagger}{ddagger}

From the {ddagger} Centre de recherche en Infectiologie du Centre de recherche du CHUL and Division de Microbiologie, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada and || Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India

The therapeutic mainstay against the protozoan parasite Leishmania is still based on the antiquated pentavalent antimonials (Sb(V)), but resistance is increasing in several parts of the world. Resistance is now partly understood in laboratory isolates, but our understanding of resistance in field isolates is lagging behind. We describe here a comparative analysis of a genetically related pair of Sb(V)-sensitive and -resistant Leishmania donovani strains isolated from kala-azar patients. The resistant isolate exhibited cross-resistance to other unrelated Leishmania drugs including miltefosine and amphotericin B. A comparative proteomics screen has highlighted a number of proteins differentially expressed suggesting that programmed cell death (PCD) is modified in the resistant parasite. Indeed drug-induced PCD progression was altered in the Sb(V)-resistant strain as determined using early and late markers of apoptosis. Two proteins, the heat shock protein HSP83 and the small kinetoplastid calpain-related protein (SKCRP14.1) were shown to be intimately implicated in the drug-induced PCD phenotype. HSP83 increased drug resistance and reduced drug-mediated PCD activation by interfering with the mitochondrial membrane potential, whereas SKCRP14.1 promoted antimonial-induced PCD but protected against miltefosine-induced PCD. This study highlights the important role of PCD in drug susceptibility/resistance in the protozoan parasite Leishmania.

{ddagger}{ddagger} A Burroughs Wellcome Fund Scholar in Molecular Parasitology and holder of a Canada Research Chair in Antimicrobial Resistance. To whom correspondence should be addressed: Centre de recherche en Infectiologie, CHUQ, pavillon CHUL, 2705 boul. Laurier, Ste.-Foy, Québec G1V 4G2, Canada. Tel.: 418-654-2705; Fax: 418-654-2715; E-mail: marc.ouellette{at}crchul.ulaval.ca


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