Mechanistic insights of the Leishmania molecules inducing macrophage-CD200 ligand: cellular phenotyping, signaling pathways involved and its application on inflammatory process during malignancies

Abstract

CD200/CD200R complex are part of the immune checkpoint regulatory system. As such, CD200 ligand plays a pivotal role in the host immune response when bound to its receptor (CD200R) by causing suppression of proinflammatory responses. While CD200R is mainly expressed in the innate immune system cells such as macrophages, CD200 is ubiquitously present in different cell types, except in macrophages when its expression is induced only at certain conditions. Previous work has shown that extracellular vesicles (EVs) containing-DNA released by intracellular Leishmania induce the expression of CD200 in macrophages, resulting in a self-inhibitory mechanism that impairs the microbicidal response mediated by iNOS/NO, favoring parasite proliferation. In this proposal, we aim to characterize inflammatory process and the content of Leishmania-EVs that induce the expression of CD200 in macrophages and elucidate the mechanisms and signaling pathways involved and the inflammatory modulation that results in inhibition of microbicidal response. Moreover, we will demonstrate the potential application of Leishmania DNA-molecules coated in charged lipid (DODAB) nanoparticles for ligand delivery to specific macrophage population in multiple models of inflammatory diseases. The results obtained in this proposal will generate mechanistic knowledge that can be applied in potential clinical interventions. Our studies are supported by a team of internal and external collaborators that will enable the discovery and potentially application in multiple disease settings. (AU)