All host/pathogen interactions rely on a constant co-evolutionary battle between genetically highly diverse microbial populations that infect equally diverse human or animal populations, with fitness gains selected both in pathogen and host through complex genotype-genotype interactions. The protozoan parasite Leishmania perfectly well illustrates this genetic cross-talk, with frequent phenotypic shifts (in pathogenicity, drug susceptibility or tissue tropism) selected in Leishmania field isolates through interactions with their heterogeneous vertebrate hosts, which in return react with very diverse clinical responses ranging from asymptomatic infection to fatal immunopathology. Despite the relevance of this highly dynamic host/pathogen relationship for disease outcome and parasite evolution, its underlying molecular mechanisms and physiological consequences remain poorly understood. To address these open questions, our team has initiated over recent years an important thematic transition from its past focus on molecular analysis of parasite signaling to its current and future focus on systems level analysis of Leishmania/macrophage interaction. This new focus animates the projects of three sub-teams that investigate (i) mechanisms of Leishmania evolutionary adaptation and fitness gain at genomic, transcriptomic and translational levels in culture, in animals (sand fly and hamster) and clinical infection (Axis 1), (ii) how Leishmania interferes in trans with macrophage functions through the exosomal release of parasite signaling proteins (Axis 2), and (iii) how Leishmania subverts macrophage immuno-metabolic functions on epigenetic and transcriptional levels to establish permissive conditions for intracellular infection (Axis 3).
