Targeting host-encoded factors for anti-leishmania therapy? Insights from chemical genetics and antimony resistant field isolates.

Leishmaniasis is a neglected tropical disease with limited therapeutic options. Thecausing agent of this disease is the obligate intracellular parasite Leishmania. This parasite develops exclusively within phagocytic cells resulting in a complex molecular interplay between the parasite and its host cell. Anti-microbial drugs classically target unique processes of the pathogen thus achieving a high antimicrobial effect and low host-cell toxicity. However, for intracellular pathogens, recent reports have underlined the potential benefits of targeting host-encoded factors that would influence pathogen invasion or intracellular proliferation. This proposal aims at understanding whether such a strategy would be applicable to anti-leishmanial therapy. The combination of two different approaches will contribute to unraveling novel host cell pathways required for Leishmania infection and intracellular growth: (1) the analysis of the infection strategies developed by a parasite resistant to a drug that partially targets host cell pathways and (2) the study of the mechanism of action of compounds specifically active against the intracellular stage of the parasite. These complementary approaches have the potential to highlight novel interactions between Leishmania and its host which would be essential to design novel and efficient therapeutics and in particular to evaluate the relevance of targeting host-encoded factors.