Abstract
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.
Highlights
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
Characterization of L. donovani Field Isolates—Lira et al [9] were the first to show that L. donovani parasites isolated from Sb(V)-unresponsive patients were resistant to Sb(V)
A selection of the same L. donovani isolates were further characterized by pulse-field gels in an attempt to find genetically related parasites that differed in their response to Sb(V) treatment
Summary
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. A comparative proteomics screen has highlighted a number of proteins differentially expressed suggesting that programmed cell death (PCD) is modified in the resistant parasite. This study highlights the important role of PCD in drug susceptibility/resistance in the protozoan parasite Leishmania. The cellular process of PCD clearly occurs at the phenotypic level in Leishmania with several cytoplasmic, mitochondrial, and nuclear features of apoptosis having been demonstrated. Even if Leishmania (and related parasites) share phenotypic similarities with PCD of multicellular organisms, it is evident that the cellular and molecular details in Leishmania are different from metazoans, and it is still not clear that every Leishmania species or even life stage uses similar PCD pathway(s) Understanding how antimonial drugs work and why they sometimes fail is fundamental to the optimal use of the existing formulations and is likely to be instructive in the development of new therapies
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