Chagas' disease, caused by Trypanosoma cruzi, is endemic to vast areas of South and Central America where it affects millions of people. Occasional cases have been reported in the United States and imported cases are often seen at American medical institutions. There is no effective chemotherapy for Chagas' disease. The few drugs currently in use can produce adverse side effects, are often ineffective in the treatment of acute Chagas' disease and are generally ineffective in the chronic stage. The exploration of the mechanisms of T. cruzi-host cell interaction (which include surface attachment, cell membrane penetration, trypomastigote -> amastigote transformation in the host cell cytoplasm and intracellular amastigote multiplication) is crucial to the identification of specific targets for effective chemotherapy. Highly promising in this regard have been our preliminary findings a) that arginine decarboxylase (ADC), an enzyme never demonstrated in mammalian cells, was detectable in blood forms of T. cruzi, b) that parasite treatment with three different drugs known to irreversibly inhibit ADC markedly reduced its capacity to infect both macrophages and myoblasts in vitro, c) that one of these inhibitors, alpha-difluoromethylarginine, strikingly inhibited the intracellular development of T. cruzi when the host cells were treated after infection and d) that a ministration of this drug to mice in their drinking water had a significant protective effect against challenge with virulent trypomastigotes and did not produce detectable toxic effects. The proposed research is specifically designed to: 1) establish which of the four stages of T. cruzi-host cell interaction mentioned above is(are) affected and to what extent; 2) define both the biochemical mechanism(s) compromised in each case and the metabolic fate of the tested agents in the parasite; and 3) investigate the effects of ADC inhibitors against experimental Chagas' disease. This study aims to clarify the role of polyamines and polyamine biosynthesis in T. cruzi infection. The results should help identify biochemical reactions in the parasite which could be targeted for effective chemotherapy.
