Visceral Leishmaniasis (VL) or Kala-Azar is a neglected tropical disease caused by Leishmania parasites that are able to survive inside macrophages. Miltefosine is an oral drug used to treat VL patients but is increasingly failing to permanently clear parasites from the patient. Parasites from these relapse patients do not seem to display an increased resistance to the drug but are able to modify the immune system to promote survival inside macrophages even in conditions where the drug is administered.
The impact of drug treatment on parasite survival will be evaluated in various tissues using molecular and imaging technologies in rodent models of VL following a natural parasite transmission. Combination of this information with the quantification of drug levels in these tissues, will allow to pinpoint in which tissues parasites are most likely to survive drug treatment. The expression of genes following infection and drug treatment will be analyzed inside infected liver macrophages (Kupffer cells, KCs) in order to understand how parasites from relapsed patients can survive inside host cells. Using transgenic mouse models, this research will allow to evaluate the impact of KCs and KC gene expression on infection and treatment outcome.
Collectively, the proposed multidisciplinary approach will improve our understanding of the complex interactions between the parasite, its host and the drug and will allow the formulation of recommendations for improved treatment interventions.