GLYCOSYLPHOSPHATIDYLINOSITOLS ARE REQUIRED FOR THE DEVELOPMENT OF TRYPANOSOMA-CRUZI AMASTIGOTES

Induction of a glycosylphosphatidylinositol (GPI) deficiency in Trypan osoma cruzi by the heterologous expression of Trypanasoma brucei GPI-p hospholipase C (GPI-PLC) results in decreased expression of major surf ace proteins (N, Garg, R L, Tarleton, and K, Mensa-Wilmot, J, Biol, Ch em, 212:12482-12491, 1997), To further explore the consequences of a G PI deficiency on replication and differentiation of T, cruzi, the in v itro and in vivo behaviors of GPI-PLC-expressing T, cruzi were studied , In comparison to wild-type controls, GPI-deficient T, cruzi epimasti gotes exhibited a slight decrease in overall growth potential in cultu re, In the stationary phase of in vitro growth, GPI-deficient epimasti gotes 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 limi ted capacity to replicate and subsequently failed to differentiate int o trypomastigotes. Mice infected with GPI-deficient parasites showed a substantially lower rate of mortality, decreased tissue parasite burd en, and a moderate tissue inflammatory response in comparison to those of mice infected,vith wild-type parasites, The decreased virulence ex hibited by GPI-deficient parasites suggests that inhibition of GPI bio synthesis is a feasible strategy for chemotherapy of infections by T, cruzi and possibly other intracellular protozoan parasites.