Leishmaniasis is a protozoan disease of high incidence and importance for animal and human health. Its causative agent, Leishmania sp, is an obligate intracellular parasite of the macrophage in its vertebrate host. As an intracellular pathogen, the progress of the infection depends inevitably on the interaction of Leishmania with the macrophage, whose relevance is accentuated because the macrophage acts as a host cell but also as a possible executor of the pathogen, in addition to being a principal orchestrator of the immune response. Current treatments for leishmaniasis are based almost exclusively on chemotherapy, threatened by increasing resistance to the few available drugs and, therefore, the search for new alternatives is urgent.
The macrophage has an enormous functional plasticity with a broad spectrum of phenotypes between two extremes: the pro-inflammatory leishmanicidal macrophage (A) and the anti-inflammatory macrophage (B) that is permissive for the parasite (see figure). This functional dichotomy includes the expression of specific markers, a particular cytokine pattern and its reciprocal association with two extreme types of energy metabolism, pro-inflammatory macrophage based on an active aerobic glycolysis in which the Krebs cycle is interrupted while the anti-inflammatory one has an active oxidative phosphorylation. The primary infection by the Leishmania promastigote initially increases the glycolysis of the macrophage, but it is subverted by the parasite in the following hours towards a functional anti-inflammatory phenotype favourable for its survival, a change in the macrophage, which in turn affects the functional polarization.
The aim of the group is to search for pharmacological strategies to metabolically force the macrophage towards a pro-inflammatory phenotype to create an unfavorable nutritional environment for the replication of the parasite, and recover its microbicidal activity. This, in turn, should increase the parasite's vulnerability to leishmanicidal drugs currently in clinical use.