Targeting Pathogens at the Site of Cellular Entry

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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. Brucellosis and tuberculosis, for which there are no cures or treatments, are major infectious agents in wild and domestic species. Furthermore, animals are major sources of infectious diseases to other animals and humans. Brucellosis is a zoonosis transmitted by direct animal-to-human contact. Other zoonoses include Leihsmania donovani, H5N1 avian influenza virus and HIV virus. Cross-species viral and bacterial infections are a constant preoccupation with respect to iatrogenic enhancement due to cross-species transmission and antibiotic resistance. It is well known that the majority of pathogens invade the cell via endocytosis, by attaching to existing cell surface receptors. Inside the cell, the pathogens trick the endosomes and lysosomes and preferentially divide within them. In eukaryotic cells the delivery of newly synthesized proteins to endosomes and lysosomes is dependent on the Golgi apparatus, i.e. the organelle that sorts and targets proteins to these destinations. Proteins delivered to endosomes and lysosomes include enzymes and activator proteins. They are directed therein via special sorting receptors. Recently, we identified a region in the lysosomal protein prosaposin that contains a motif required for its binding to the sorting receptors sortilin and consequently for its transport to endosomes and lysosomes. In this proposal we will test the hypothesis that fusion proteins linked to this motiff can be transported to the endo/lysosomal compartment via sortilin, and that this sequence may be useful for the targeting of anti-pathogenic proteins. Our study will permit to establish a proof of concept of a new strategy for the targeting of antimicrobial proteins to 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.