Treatment failure in leishmaniasis: host sanctuary sites and parasite quiescence.
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.Researcher(s)
- Promoter: Caljon Guy
- Co-promoter: Dirkx Laura
- Fellow: Nicolaes Yasmine
Research team(s)
Project type(s)
- Research Project
Characterizing the bone marrow as a parasitological niche responsible for antileishmanial treatment failure.
Abstract
Visceral Leishmaniasis (VL) or Kala-Azar is a neglected tropical disease caused by Leishmania parasites that are transmitted by sand flies. Paromomycin (PMM) is used to treat VL patients but was experimentally shown to rapidly induce resistance when applied as a single therapy. We have recently observed that parasites overcome elimination by PMM by hiding in the bone marrow (BM) from where the host can be recolonized. Using combined bioluminescent/fluorescent L. infantum reporter lines with differential susceptibility to PMM, this project will make an in depth analysis of the different cell types in the BM that are infected with L. infantum. Parasite survival in various BM cell types will be evaluated to identify potential sanctuary cells. Parasite isolates from the BM of mice and human patients will be used to explore the acquisition of PMM-resistance in relation to parasite virulence. Infectivity for macrophages and transmissibility by sand flies will serve as indicators for the likelihood of posttreatment parasites to spread. Parallels with treatment of myeloid leukemia, indicate that modulating a specific pathway in hematopoiesis that regulates the BM cellular composition could enhance the efficiency of chemotherapy for VL. 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.Researcher(s)
- Promoter: Caljon Guy
- Co-promoter: Maes Louis
- Fellow: Dirkx Laura
Research team(s)
Project type(s)
- Research Project