Stage-dependent role of nitric oxide in control of Trypanosoma cruzi infection

Trypanosoma cruzi, the causative agent of Chagas' disease, is known to be s usceptible to nitric oxide (NO)-dependent killing by gamma interferon-activ ated macrophages. Mice deficient for inducible nitric oxide synthase (iNOS) are highly susceptible to T. cruzi, and inhibition of iNOS from the beginn ing of infection was reported to lead to an increase in trypomastigotes in the blood and to high mortality. In the present study, we investigated whet her NO production is essential for the control of T. cruzi in all phases of the infection. BALB/c mice were treated at different time intervals after T. cruzi infection with an iNOS inhibitor, aminoguanidine or L-N-6-(1-imino ethyl)-lysine (L-NIL). Treatment initiated with the beginning of the infect ion resulted in 100% mortality by day 16 postinfection (p.i.), If treatment was started later during the acute phase at the peak of parasitemia (day 2 0 p.i.), all the mice survived. Parasitemia was cleared and tissue amastigo tes became undetectable in these mice even in the presence of the iNOS inhi bitor L-NIL. Inhibition of iNOS in the chronic phase of the infection, i.e. , from day 60 to day 120 p.i., with L-NIL did not result in a reappearance of parasitemia; These data suggest that while NO is essential for T. cruzi control in the early phase of acute infection, it is dispensable in the lat e acute and chronic phase, revealing a fundamental difference in control me chanisms compared to those in infections by other members of the order Kine toplastida, e.g., Leishmania major.