Towards new concepts in anti-Leishmania treatment by modifying the interplay between sand fly transmitted parasites and the host innate immune system

Leishmaniasis is a major neglected parasitic disease with a broad range of clinical manifestations including the lethal visceral disease. New drug discovery initiatives are essential given the serious adverse effects of current treatments and/or the increasing threat of drug resistance development. The present project aims to contribute towards novel concepts on intervention strategies that could bypass some problems relating to drug failure. Through the establishment of a sand fly colony, host-parasite interactions such as parasite virulence, disease-associated immunity and pathology, and treatment efficacy will be studied in laboratory rodent models that include the insect vector. The vector component will also allow improved antileishmanial lead characterization, drug resistance research and adaptation of clinical isolates to in vitro and in vivo laboratory models enabling improved monitoring of treatment efficacy in the field. This study will explore the interplay of host immune cells (neutrophils and monocytes) with recent clinical isolates and laboratory strains showing significant differences in virulence that arise from the acquisition of drug resistance. Responses will be studied by using a state-of-the art kinomics platform, that allows a straightforward acquisition of phenotypic fingerprints of intracellular kinase activation. This will provide cutting-edge information on the parasite-host interplay and on inflammation in general. Knowing that neutrophils have been ascribed infection-promoting activities, selective targeting of innate immune cell function will be explored as a complementary asset to control parasitic infections. This has not yet been explored, although anticipated to be much less prone to the development of resistance mechanisms. This approach could possibly also support the identification of novel drug or vaccine targets.

Keywords:INFECTIONS, PARASITOLOGY, LEISHMANIA

Disciplines:Microbiology, Veterinary medicine