Epigenetic immune subversion in Leishmania macrophage infection – ELATION

Many viral, bacterial and eukaryotic pathogens have co-evolved strategies to modulate the expression profile of their mammalian host cells promoting their own survival. Underlying regulatory mechanisms are only poorly understood, despite their relevance in human disease and host-directed therapy. ELATION synergizes the complementary expertise of its partners in host/pathogen interaction and chemical biology to investigating the role of epigenetic regulation in the subversion of macrophage immuno-metabolic functions during intracellular infection with the protozoan parasite Leishmania. These important pathogens can harness the macrophage phenotypic potential to favor their intracellular survival, thereby causing a spectrum of severe immuno-pathologies termed leishmaniases.
We have recently published first evidence that Leishmania infection causes histone H3 hypomethylation at pro-inflammatory promoters of infected macrophages, which correlated to severe immune suppression. A previous collaboration of both partner teams further discovered a series of inhibitors targeting the macrophage epigenetic enzyme ‘lysine specific demethylase 1’ (LSD1, aka KDMT1a), which caused elimination of intracellular Leishmania in a host-directed fashion. Together these results lend strong support to our major working hypothesis that Leishmania subverts macrophage LSD1 functions to establish permissive conditions for intracellular parasite survival, and suggests LSD1 as a first target for host-directed, anti-leishmanial therapy.
ELATION capitalizes on our recent discoveries and applies a highly innovative ChemBio approach novel in immunological research, to unravel epigenetic mechanisms of immune subversion underlying intracellular infection and the development of pathological polarization states of macrophages. These goals will be achieved through three complementary objectives: Objective 1 maps infection- and LSD1-dependent changes of the macrophage epigenome combining ATACseq, CUT&RUN and ChemSeq approaches, that together will establish a first genome-wide view of chromatin accessibility, histone H3 modification, and LSD1 promoter occupancy. Objective 2 applies two complementary loss-of-function strategies to study the impact of chemical and genetic LSD1 ablation on Leishmania intracellular survival, on the macrophage immuno-metabolic expression profile, and on macrophage epigenetic regulation. Finally, Objective 3 uses the power of dCas9-guided, locus specific chromatin precipitation and LSD1 inhibitor delivery to identify qualitative and quantitative changes in LSD1 complex formation and to establish the biological relevance of LSD1-regulated genes in Leishmania survival.
Our project will overcome important scientific, translational, and technical barriers relevant to other intracellular infections, such as tuberculosis, candidiasis, AIDS or COVID. First, applying Leishmania as a model pathogen will have immediate scientific impact on our understanding of (i) epigenetic regulation in host/pathogen interaction and macrophage immune subversion, (ii) macrophage phenotypic plasticity and its pathogenic potential, and (iii) the role of LSD1 in regulating the transition of immuno-competent macrophages into a permissive environment for Leishmania and likely other macrophage-infecting microbes. Second, the basic-science validation by ELATION of mammalian LSD1 inhibitors as new, anti-leishmanial drug candidates, delivers important translational potential and opens exciting new possibilities to repurpose existing epigenetic and metabolomic drugs for host-directed therapy. Finally, ELATION capitalizes on these established LSD1 inhibitors to develop a series of innovative chemical probes, which will establish a novel experimental framework in the study of host/parasite interaction and microbial innate immune evasion relevant to Leishmania but also many other pathogens that exploit these essential immune cells as hosts.