Finding the cause of leishmaniasis relapse after treatment with miltefosine using untargeted proteomics.

The protozoan parasite Leishmania donovani is responsible for the disease visceral leishmaniasis (VL) in the Indian Subcontinent. Each year, an estimated 200 000-400 000 people contract VL, which is almost always fatal if left untreated. Sodium stibogluconate (SSG) has been used for decades for the treatment of leishmaniasis, but is now being replaced by miltefosine (MIL) and amphotericin B due to toxicity and widespread drug resistance. However, recent reports indicate a significant decrease in the efficacy of MIL with 20% of the patients relapsing within 12 months after treatment. Remarkably, and in contrast with SSG resistance, this relapse could not be related to reinfection, drug quality, drug exposure, or drug-resistant parasites which poses major questions about the cause of this treatment relapse. In a previous study we showed that parasites isolated from MIL relapse patients did have a different phenotype compared to the MIL cure Leishmania donovanii. However, it is not clear what the molecular basis of this difference is, if it is causal or not, and if other mechanisms could be involved. Therefore, the goal of this study is to find which molecular features are causing the observed leishmaniasis relapse after MIL treatment and the related increase in infectivity. Untargeted 'omics studies are particularly suited for this task, since in this case, there is no prior knowledge of which mechanisms could be involved. Out of all functional levels (genome, transcriptome, proteome and metabolome) the proteome is the level that translates genomic variety into metabolic and functional changes. Therefore, this study will characterize the proteomic differences between MIL cure and MIL relapse Leishmania isolates in order to find out what is causing this relapse.

Keywords:PROTEOMICS, LEISHMANIA

Disciplines:Applied mathematics in specific fields