Leishmaniases is a serious communicable disease endemic in more than 80 countries around the world: most of them are tropical or sub-tropical countries, but in contrast to other ’tropical’ diseases, leishmaniasis is also endemic in Southern Europe. The disease is caused by several species of Leishmania, and is transmitted through the bite of sand flies. Several clinical forms are encountered, the two most severe being the muco-cutaneous (MCL) and visceral (VL) leishmaniases...
Chemotherapy is critically important in reducing the burden of disease and antimonials (SbV) are the first line drug for all clinical forms. Treatment is long, toxic and expensive because of drug cost and hospitalisation. Besides a few alternative drugs like AmphotericinB or Miltefosine (MILT), there are no other drugs in the pipeline.
In that context, it is essential to protect current drugs against the emergence of resistance. Treatment failure is well documented for SbV. Most alarming reports came from Bihar (India), where over 60% of patients with visceral leishmaniasis (VL) do not respond to SbV-treatment (Sundar S, 2001). Using directly observed treatment (DOT), we documented 5 to 24% failure in Nepal, another country endemic for VL, and 20-40% failure in Peru (American tegumentary leishmaniasis). Treatment failure can be due to host or drug factors, but in all the countries mentioned above parasites intrinsically resistant to SbV were encountered. Monitoring drug resistance is thus essential and is currently done by labour-intensive biological assays in which the inhibitory doses of the drug are measured in an in vitro macrophage infection model. Molecular detection tools would constitute a rapid and high throughput alternative. Several mechanisms leading to experimentally induced resistance to SbV have been described (), but so far they (i) were not tested on naturally resistant parasites, neither (ii) translated into relevant detection tools.
Our main goal is to develop and evaluate molecular tools for the detection of natural resistance of Leishmania to SbV.
We will focus on VL in an epidemiological situation (Nepal) that we have been exploring since several years and in which we have been gathering high quality information about SbV failure. We now possess a unique and large collection of: (i) L.donovani strains naturally sensitive (S) or resistant (R) to SbV and (ii) clinical samples from Nepalese patients responding or not to SbV.
Our specific objectives are:
- To identify, among the markers reported in experimentally induced SbV resistance, the ones which best correlate with natural resistance in our collection of L.donovani strains.
- To verify experimentally the involvement of the selected markers in the in vitro resistance.
- To develop molecular tools to detect markers of SbV resistance in clinical samples of patients
- To test the correlation between the presence of the markers and SbV treatment failure