Laura Dirkx postdoc researcher FWO

Research Laura Dirkx

Research team

A quest for mechanisms and biomarkers of post-treatment relapse during visceral leishmaniasis. 01/10/2024 - 30/09/2027

Abstract

In the last decade, stem cells have been discovered to serve as a reservoir for many pathogenic organisms. Our recent research on visceral leishmaniasis (VL) revealed that hematopoietic stem cells (HSC) in the bone marrow underlie treatment failure and relapse. These cells exhibit a unique transcriptional signature (StemLeish) and provide an environment for the development of parasite quiescence, a metabolic state that is impervious to drug treatment. This project will build upon these cutting-edge findings in order to obtain (i) a thorough characterization of immunological processes in the HSC niche that are at the basis of treatment failure, and (ii) mechanistic insights in the possible trigger(s) of VL relapse and the particular role of Macrophage Migration Inhibitory Factor (MIF). From an applied research viewpoint, this project will (iii) establish the diagnostic value of HSC biomarkers using patient samples and (iv) install a novel drug screening platform based on the developed tools to predict and capture the risk of relapse. It is expected that this project will open new therapeutic avenues that may extend beyond leishmaniasis and be revolutionary in the precarious battle against treatment failure.

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  • Research Project

Treatment failure in leishmaniasis: host sanctuary sites and parasite quiescence. 01/11/2022 - 31/10/2026

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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  • Research Project

Characterizing the bone marrow as a parasitological niche responsible for antileishmanial treatment failure. 01/01/2019 - 31/12/2022

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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Project type(s)

  • Research Project