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HEIndividual fellowship2023–2025

LeishMOM · Inadequate migration of Leishmania-infected macrophages – the driver of parasite dissemination?

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-09-01 → 2025-08-31
EU contribution
€189,687
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

Inadequate migration of Leishmania-infected macrophages – the driver of parasite dissemination?

Leishmaniasis is a major neglected tropical disease, with over one million new cases and approximately 20,000 deaths reported annually. Transmitted through the bite of infected sand flies, Leishmania parasites invade macrophages, subverting these immune cells to survive and replicate. Depending on the infecting species, disease manifestations range from localised cutaneous lesions (cutaneous leishmaniasis [CL]) to fatal visceral infections (visceral leishmaniasis [VL]). The difference between a mild and a life-threatening form of disease is largely determined by how the parasite disseminates within the host, yet the mechanisms driving this dissemination remain poorly defined. Previous work suggests that Leishmania species can manipulate macrophage migration in a species-dependent manner. Understanding how Leishmania species hijack host migration pathways is essential for identifying new therapeutic strategies that target host-pathogen interactions. This project set out to test the hypothesis that Leishmania species modulate macrophage migration in a species-specific manner. The work was structured around two main objectives: 1. To compare the spatiotemporal migration behaviour of macrophages infected with species causing cutaneous and visceral leishmaniasis. 2. To identify host macrophage genes and molecular pathways underlying these migration phenotypes using CRISPR knockout and drug-inhibitor screens.

Data: CORDIS, © European Union

Project objective

Leishmania parasites, a threat to 350 million people worldwide, are transmitted by sand flies and reside predominantly intracellularly in macrophages. Leishmania species can remain local (cutaneous leishmaniasis) or spread throughout the tissue and body (mucocutaneous/visceral leishmaniasis). This is the difference between a mild illness or a deadly disease, and the fundamental mechanisms behind these different clinical manifestations are largely unknown. As Leishmania parasites seem immobile following their delivery into the skin and are rapidly phagocytosed, it has been hypothesised that dissemination is driven by host cell migration in a species-dependent manner. Specifically, previous studies showed that Leishmania species causing visceral infections typically enhance macrophage motility, while species linked to cutaneous lesions slow down infected macrophages. However, few studies have directly compared migration of parasitised macrophages across multiple Leishmania species and it remains unclear which host migration pathways Leishmania manipulates. We want to test the hypothesis that different Leishmania species alter integrin-dependent and –independent macrophage migration modes in distinct ways, to control dissemination through the dermis and across endothelial barriers. Using human skin equivalents, cell deformability assays, and two- and three-dimensional migration assays, we will measure changes in migration dynamics of Leishmania-infected macrophages. Additionally, we will perform drug inhibitor and CRISPR screens, targeting macrophage genes, to identify host pathways essential for migration of parasitised macrophages. To dissect species-related differences, this study will use species causing visceral, mucocutaneous, and cutaneous leishmaniasis. The results will give insights into Leishmania dissemination mechanisms, thereby facilitating future designs of new therapeutics aimed at controlling inadequate migration of infected macrophages.

Original text from CORDIS.

Participants

  • JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG · WuerzburgCoordinatorGermany

Links

Data: CORDIS, © European Union