title: Antimonial resistance in Leishmania donovani is associated with increased in vivo parasite burden.
abstract: Leishmania donovani is an intracellular protozoan parasite that causes visceral leishmaniasis (VL). Antimonials (SSG) have long been the first-line treatment against VL, but have now been replaced by miltefosine (MIL) in the Indian subcontinent due to the emergence of SSG-resistance. Our previous study hypothesised that SSG-resistant L. donovani might have increased in vivo survival skills which could affect the efficacy of other treatments such as MIL. The present study attempts to validate these hypotheses. Fourteen strains derived from Nepalese clinical isolates with documented SSG-susceptibility were infected in BALB/c mice to study their survival capacity in drug free conditions (non-treated mice) and in MIL-treated mice. SSG-resistant parasites caused a significant higher in vivo parasite load compared to SSG-sensitive parasites. However, this did not seem to affect the strains' response to MIL-treatment since parasites from both phenotypes responded equally well to in vivo MIL exposure. We conclude that there is a positive association between SSG-resistance and in vivo survival skills in our sample of L. donovani strains which could suggest a higher virulence of SSG-R strains compared to SSG-S strains. These greater in vivo survival skills of SSG-R parasites do not seem to directly affect their susceptibility to MIL. However, it cannot be excluded that repeated MIL exposure will elicit different adaptations in these SSG-R parasites with superior survival skills compared to the SSG-S parasites. Our results therefore highlight the need to closely monitor drug efficacy in the field, especially in the context of the Kala-azar elimination programme ongoing in the Indian subcontinent.
authors.affiliation: Unit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Manu
authors.initials: M
authors.lastname: Vanaerschot
authors.forename: Simonne
authors.initials: S
authors.lastname: De Doncker
authors.forename: Suman
authors.initials: S
authors.lastname: Rijal
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
authors.forename: Saskia
authors.initials: S
authors.lastname: Decuypere
mesh_terms: D000818:Animals; D000965:Antimony / Q000494:pharmacology* / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004351:Drug Resistance; D007194:India; D007893:Leishmania donovani / Q000187:drug effects* / Q000302:isolation & purification; D008099:Liver / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000627:therapeutic use; D013154:Spleen / Q000469:parasitology
chemical_list: D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine; D000965:Antimony