Glycosylphosphatidylinositols are required for the development of Trypanosoma cruzi amastigotes

Induction of a glycosylphosphatidylinositol (GPI) deficiency in Trypanosoma cruzi by the heterologous expression of Trypanasoma brucei GPI-phospholipase C (GPI-PLC) results in decreased expression of major surface proteins (N, Garg, R L, Tarleton, and K, Mensa-Wilmot, J, Biol, Chem, 212:12482-12491, 1997), To further explore the consequences of a GPI deficiency on replication and differentiation of T, cruzi, the in vitro and in vivo behaviors of GPI-PLC-expressing T, cruzi were studied, In comparison to wild-type controls, GPI-deficient T, cruzi epimastigotes exhibited a slight decrease in overall growth potential in culture, In the stationary phase of in vitro growth, GPI-deficient epimastigotes readily converted to metacyclic trypomastigotes and efficiently infected mammalian cells, However, upon conversion to amastigote forms within these host cells, the GPI-deficient parasites exhibited a limited capacity to replicate and subsequently failed to differentiate into trypomastigotes. Mice infected with GPI-deficient parasites showed a substantially lower rate of mortality, decreased tissue parasite burden, and a moderate tissue inflammatory response in comparison to those of mice infected,vith wild-type parasites, The decreased virulence exhibited by GPI-deficient parasites suggests that inhibition of GPI biosynthesis is a feasible strategy for chemotherapy of infections by T, cruzi and possibly other intracellular protozoan parasites.