Epigenetic subversion in Leishmania macrophage infection (ELATION)

• Applicant: Professor Dr. Manfred Jung
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Pharmacy
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 490929945

Dysregulation of epigenetic control has been recognized as a major source of human disease, ranging from cancer to microbial infection. Many viral, bacterial and eukaryotic pathogens infect mammalian cells and have co-evolved strategies to modulate the expression profile of their host cells promoting their own survival. Despite the devastating consequences for human health, the epigenetic mechanisms underlying such host cell subversion are only poorly understood. Here we apply the protozoan parasite Leishmania as a unique model system to lift this major scientific barrier by investigating the epigenetic mechanisms that allow these parasites to evade macrophage immuno-metabolic functions and to exploit these essential immune cells for intracellular survival. Preliminary work revealed a series of inhibitors targeting the macrophage epigenetic enzyme ‘lysine specific demethylase 1’ (LSD1) that lead to killing of intracellular Leishmania in a host-directed fashion. We propose that Leishmania subverts macrophage LSD1 functions to establish permissive conditions for intracellular parasite survival and that investigating LSD1 functions in our system will provide new insight into epigenetic mechanisms underlying intracellular infection and the development of pathological macrophage polarization states. We will develop innovative chemical biology tools that will strongly contribute to the understanding of the role of host cell LSD1 in macrophage infection. Specifically, biotinylated LSD1 inhibitors will be powerful tools for ChemSeq, chemical degraders (PROTACs) of LSD1 will allow chemically driven loss-of-function studies and dCas9-mediated prodrug release will allow subcellular control of epigenetic inhibitor action. Thus, the combined and synergistic expertise of the applicants will deliver deep mechanistic insight into epigenetic macrophage subversion by Leishmania which in addition will serve as a blueprint to study other intracellular infections.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Professor Dr. Gerald Späth