Comparison of gene expression patterns among Leishmania braziliensis clinical isolates showing a different in vitro susceptibility to pentavalent antimony.
BACKGROUND
Evaluation of Leishmania drug susceptibility depends on in vitro Sb(V) susceptibility assays, which are labour-intensive and may give a biased view of the true parasite resistance. Molecular markers are urgently needed to improve and simplify the monitoring of Sb(V)-resistance. We analysed here the gene expression profile of 21 L. braziliensis clinical isolates in vitro defined as Sb(V)-resistant and -sensitive, in order to identify potential resistance markers.


METHODS
The differential expression of 13 genes involved in Sb(V) metabolism, oxidative stress or housekeeping functions was analysed during in vitro promastigote growth.


RESULTS
Expression profiles were up-regulated for 5 genes only, each time affecting a different set of isolates (mosaic picture of gene expression). Two genes, ODC (ornithine decarboxylase) and TRYR (trypanothione reductase), showed a significantly higher expression rate in the group of Sb(V)-resistant compared to the group of Sb(V)-sensitive parasites (P<0.01). However, analysis of individual isolates showed both markers to explain only partially the drug resistance.


CONCLUSIONS
Our results might be explained by (i) the occurrence of a pleiotropic molecular mechanism leading to the in vitro Sb(V) resistance and/or (ii) the existence of different epi-phenotypes not revealed by the in vitro Sb(V) susceptibility assays, but interfering with the gene expression patterns.
Adaui
V
V
Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.
Schnorbusch
K
K
Zimic
M
M
Gutiérrez
A
A
Decuypere
S
S
Vanaerschot
M
M
DE Doncker
S
S
Maes
I
I
Llanos-Cuentas
A
A
Chappuis
F
F
Arévalo
J
J
Dujardin
J-C
JC
D000818:Animals; D000965:Antimony / Q000494:pharmacology* / Q000627:therapeutic use; D018929:Cell Culture Techniques; D004351:Drug Resistance / Q000235:genetics*; D020869:Gene Expression Profiling; D058685:Genetic Pleiotropy; D014644:Genetic Variation; D006801:Humans; D007892:Leishmania braziliensis / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000235:genetics* / Q000469:parasitology; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D021261:Parasitic Sensitivity Tests
D000965:Antimony; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D009955:Ornithine Decarboxylase