Discovery of novel drug-resistance genes involved in lipid regulation of cell membrane structure and their impact in canine leishmaniasis treatment failure

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Canine leishmaniosis (CanL) is a parasite-borne disease mainly caused by Leishmania infantum. Life-threatening L. infantum infects domestic and wild dogs that subsequently develop different clinical presentations ranging from mild presentations to fatal disease. Furthermore, these infected dogs act as a major reservoir and foci of transmission of resistant Leishmania strains to humans. This dangerous zoonotic disease is increasingly affecting countries where it was previously unknown or had been eradicated for a long time. Traditionally, CanL threatened canine species in Europe and South America. However, alarming evidences point to the introduction of this fatal zoonotic disease into the canine populations of Canada and the United States. Despite many vaccine-development efforts have been carried during the last decade, none of has raised as a true alternative to chemotherapy in dogs. The elevated cost of these treatments (an average of $6 000 USD), has triggered unethical dog culling as the only solution to tackle the disease in many endemic countries. In the absence of new drugs introduced in the recent years, current CanL antileishmanials are restricted to only two drugs, old-fashioned antimonial derivatives and antitumor-drug miltefosine. While it is true they are still effective against sensitive Leishmania populations that have never been put in contact with them, their massive use during the last years, coupled to the high ability of these parasites to adapt and survive external stress (including drug pressure), has triggered the rapid emergence and spread of highly resistant populations that are easily transmitted from animals to humans, and vice versa. An additional problem is current antileishmanials have neither well-defined mechanism of action nor mechanism of resistance. Interestingly, the two main drugs currently used for treating CanL, as well as the strongest second line alternative (amphotericin B), seem to induce resistance in Leishmania through major changes in the composition of parasite's cellular lipids and alteration of its cellular membrane fluidity. The here-proposed Research Program aims to discover and investigate novel lipid-related molecular characters responsible for the development of drug resistance in Leishmania. Since such knowledge is currently lacking, our findings will be essential for the development of novel treatments based on experimental molecules that target and/or interact with membrane components. We truly expect the outcomes and knowledge generated in this Research Program, in addition to train highly qualified veterinary-parasitology researchers, will positively impact on future CanL treatment and control by reducing the numbers of slaughtered dogs, dog suffering, resistance emergence, clinical relapse and zoonotic-transmission risk to humans.