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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024874-03
Application #
3138132
Study Section
Biochemistry Study Section (BIO)
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1991-09-01
Budget End
1994-08-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Schettino, P M; Majumder, S; Kierszenbaum, F (1995) Regulatory effect of the level of free Ca2+ of the host cell on the capacity of Trypanosoma cruzi to invade and multiply intracellularly. J Parasitol 81:597-602
Majumder, S; Kierszenbaum, F (1993) Inhibition of host cell invasion and intracellular replication of Trypanosoma cruzi by N,N'-bis(benzyl)-substituted polyamine analogs. Antimicrob Agents Chemother 37:2235-8
Majumder, S; Kierszenbaum, F (1993) N,N'-thiophene-substituted polyamine analogs inhibit mammalian host cell invasion and intracellular multiplication of Trypanosoma cruzi. Mol Biochem Parasitol 60:231-9
Yakubu, M A; Majumder, S; Kierszenbaum, F (1993) Inhibition of S-adenosyl-L-methionine (AdoMet) decarboxylase by the decarboxylated AdoMet analog 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811) decreases the capacities of Trypanosoma cruzi to infect and multiply within a mammalian J Parasitol 79:525-32
Majumder, S; Wirth, J J; Bitonti, A J et al. (1992) Biochemical evidence for the presence of arginine decarboxylase activity in Trypanosoma cruzi. J Parasitol 78:371-4
Yakubu, M A; Basso, B; Kierszenbaum, F (1992) DL-alpha-difluoromethylarginine inhibits intracellular Trypanosoma cruzi multiplication by affecting cell division but not trypomastigote-amastigote transformation. J Parasitol 78:414-9
Rodriguez de Cuna, C; Kierszenbaum, F; Wirth, J J (1991) Binding of the specific ligand to Fc receptors on Trypanosoma cruzi increases the infective capacity of the parasite. Immunology 72:114-20