Trypanosoma cruzi causes Chagas' disease, a chronic debilitating, incurable condition afflicting millions of people in Latin America. Although the mechanisms governing the interactions of the trypanosomes with mammalian and invertebrate hosts remain unknown, recent information implicate the trans-sialidase as a virulence factor in Chagas' disease. Trans-sialidase is a developmentally regulated enzyme most specific for alpha2,3-linked sialic acid. It is located on the surface of infective trypomastigote and of insect form epimastigote, but it is absent from amastigote. The trans-sialidase promotes parasite attachment to mammalian cells in culture and enhances T. cruzi virulence in the murine model of Chagas' disease. This project addresses the mechanism underlying the virulence-enhancing effect of the trans-sialidase. Experiments will be performed in vivo in a mammalian host model (mouse) and in an invertebrate host (the insect Rhodnius prolixus). Experiments will also be performed in vitro with culture cells. Course of infection will be followed with probes that react with the trans-sialidase, with intact and fragments of trans- sialidase as competitive inhibitors, as well as with trans-sialidase inhibitors developed by Dr. Mark von Itzstein in Project 4. The result of these studies could have a significant impact in the understanding of T. cruzi-host (vertebrate and invertebrate) interactions and in the chemotherapy of Chagas' disease.
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