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

ended

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.