A novel Approach to Target Trypanosome, Leishmania and Superbugs to the Lysosomal Compartment

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The long term objective of this research is to develop a novel therapeutic approach that will revolutionize the way transmissible diseases are treated, by offering an alternative therapy to antiviral drugs, antibiotics and vaccines. Trypanosomiasis (Trypanosoma spp.), leishmaniosis (Leishmania spp.), brucellosis (Brucella spp.), and tuberculosis (Mycobacterium spp.), for which there are no effective cures or treatments are major infectious agents in wild species, domestic animals and humans. It is well known that the majority of pathogens invade the cell via endocytosis, by attaching to existing cell surface receptors. Once inside the cell, the pathogens trick the phagosomes and lysosomes and preferentially divide within them. In eukaryotic cells the delivery of newly synthesized proteins to endosomes, phagosomes and lysosomes is dependent on the Golgi apparatus, i.e., the organelle that sorts and targets proteins to these destinations. Proteins delivered to endosomes, phagosomes and lysosomes include enzymes and activator proteins. They are directed therein via special sorting receptors. We found that a region in the lysosomal activator protein “Prosaposin” (PSAP) contains a motif required for its binding to a sorting receptor called “Sortilin” and consequently for its transport to the endolysosomal compartment. During our last “NSERC Grant” we demonstrated that the antimicrobial proteins β-Defensin and Tachyplesin linked to the lysosomal targeting motif of PSAP were delivered to endosomes and lysosomes. In this proposal, we would like to test the following hypotheses: 1) β-Defensin-PSAP and Tachyplesin-PSAP are directed to the endolysosomal system via Sortilin; 2)Tachyplesin-PSAP has trypanocidal and leishmanocidal effects in the lysosomal compartment of infected cells; 3) β-Defensin-PSAP has a bactericidal effect in the lysosomal compartment of infected cells. Thus, the present study will assess the effectiveness of these antimicrobial fusion proteins to kill trypanosomes, leishmania and bacteria within phagosomes and lysosomes. Our study will permit to establish a proof of concept of a new strategy for the elimination of pathogens in the endo/lysosomal compartment. The outcome of our research will be relevant for the treatment of infectious diseases in wild, endangered, and domestic animal species, as well as in humans and will open innumerable avenues to examine the delivery and effects of antipathogenic peptides in viral, bacterial and protozoal infections.***