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Modulation of Gene Expression in Human Macrophages Treated with the Anti-Leishmania Pentavalent Antimonial Drug Sodium Stibogluconate ^,

Karima El Fadili, Michaël Imbeault, Nadine Messier, Gaétan Roy, Benjamin Gourbal, Marc Bergeron, Michel J. Tremblay, Danielle Légaré, and Marc Ouellette^*

Centre de Recherche en Infectiologie du Centre de Recherche du CHUL and Division de Microbiologie, Faculté de Médecine, Université Laval, Québec, Canada

Received 7 September 2007/ Returned for modification 1 November 2007/ Accepted 26 November 2007

Within the mammalian host, Leishmania donovani is an obligatory intracellular protozoan parasite that resides and multiplies exclusively in the phagolysosomes of macrophages. Leishmania control relies primarily on chemotherapy, with the mainstay being pentavalent antimony (SbV) complexed to carbohydrates in the form of sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime). The mode of action of SbV is still not known precisely. To explore the effect of SbV on macrophage gene expression, a microarray analysis was performed using Affymetrix focus arrays to compare gene expression profiles in noninfected and L. donovani-infected THP-1 monocytic cells treated or not treated with sodium stibogluconate. Under our experimental conditions, SbV changed the expression of a few host genes, and this was independent of whether cells were infected or not infected with Leishmania. Leishmania infection had a greater effect on the modulation of host gene expression. Statistical analyses have indicated that the expression of eight genes was modified by at least twofold upon SbV treatment, with six genes upregulated and two genes downregulated. One gene whose expression was affected by SbV was the heme oxygenase gene HMOX-1, and this change was observed both in the monocytic cell line THP-1 and in primary human monocyte-derived macrophages. Another pathway that was affected was the glutathione biosynthesis pathway, where the expression of the glutamate-cysteine ligase modifier subunit was increased upon SbV treatment. Our analysis has suggested that, under our experimental conditions, the expression of a few genes is altered upon SbV treatment, and some of these encoded proteins may be implicated in the yet-to-be-defined mode of action of SbV.

Published ahead of print on 10 December 2007.

Supplemental material for this article may be found at http://aac.asm.org/.

Present address: Parasitologie Fonctionnelle et Evolutive, UMR 5244, CNRS Université de Perpignan.