Abstract
Visceral leishmaniasis (VL) is a lethal parasitic disease facing a rise of treatment failures with current drugs. Major knowledge gaps exist in the basis of treatment failure, representing an essential constraint in the development of long-term effective drugs. Our cutting-edge research has recently identified the bone marrow as a sanctuary site where parasites can hide and survive drug treatment. Combination of large-scale in vivo drug screening and immunophenotyping identified stem cells as highly susceptible host cells. These cells exhibit a unique transcriptional "StemLeish" program and provide an environment for the development of parasite quiescence, a metabolic state that enables survival of drug treatment. This project will provide unprecedented information about the host- and parasite-factors underlying relapse by (i) obtaining essential data on the infection and spreading potential of quiescence-associated traits, (ii) deciphering the role of Stemleish genes in stem cell sanctuary and in stimulation of parasite quiescence, with identification of parasite driver/marker genes, and (iii) exploring the therapeutic and diagnostic applications of these novel targets and biomarkers. Taken together, it is expected that in-depth understanding of the molecular basis of stem cells as a parasite niche will be revolutionary for VL treatment and will generate potential diagnostic/prognostic tools that incorporate host sanctuary properties and parasite quiescence features.
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