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.
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