Glycosylphosphatidylinositols are required for the development of Trypanosoma cruzi amastigotes.
Induction of a glycosylphosphatidylinositol (GPI) deficiency in Trypanosoma cruzi by the heterologous expression of Trypanosoma 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. 272:12482-12491, 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 with 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.
Garg
N
N
Department of Cellular Biology, University of Georgia, Athens 30602, USA.
Postan
M
M
Mensa-Wilmot
K
K
Tarleton
R L
RL
D000818:Animals; D014355:Chagas Disease / Q000469:parasitology; D005260:Female; D054800:Glycosylphosphatidylinositol Diacylglycerol-Lyase; D017261:Glycosylphosphatidylinositols / Q000172:deficiency*; D051379:Mice; D008809:Mice, Inbred C3H; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D014349:Trypanosoma cruzi / Q000254:growth & development* / Q000472:pathogenicity*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics
D017261:Glycosylphosphatidylinositols; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054800:Glycosylphosphatidylinositol Diacylglycerol-Lyase