Activation of host cell phosphatidylinositol 3-kinases by Trypanosoma cruzi infection.
Trypanosoma cruzi, the causative agent of Chagas' disease in humans, is an intracellular protozoan parasite with the ability to invade a wide variety of mammalian cells by a unique and remarkable process in cell biology that is poorly understood. Here we present evidence suggesting a role for the host phosphatidylinositol (PI) 3-kinases during T. cruzi invasion. The PI 3-kinase inhibitor wortmannin marked inhibited T. cruzi infection when macrophages were pretreated for 20 min at 37 degrees C before inoculation. Infection of macrophages with T. cruzi markedly stimulated the formation of the lipid products of the phosphatidylinositol (PI) 3-kinases, PI 3-phospate, PI 3,4-biphosphate, and PI 3,4,5-triphosphate, but not PI 4-phosphate or PI 4,5-biphosphate. This activation was inhibited by wortmannin. Infection with T. cruzi also stimulated a marked increase in the in vitro lipid kinase activities that are present in the immunoprecipitates of anti-p85 subunit of class I PI 3-kinase and anti-phosphotyrosine. In addition, T. cruzi invasion also activated lipid kinase activity found in immunoprecipitates of class II and class III PI 3-kinases. These data demonstrate that T. cruzi invasion into macrophages strongly activates separated PI 3-kinase isoforms. Furthermore, the inhibition of the class I and class III PI 3-kinase activities abolishes the parasite entry into macrophages. These findings suggest a prominent role for the host PI 3-kinase activities during the T. cruzi infection process.
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro 21941-900, Brazil.
A G
AG
Todorov
M
M
Einicker-Lamas
S L
SL
de Castro
M M
MM
Oliveira
A
A
Guilherme
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000145:classification / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000469:parasitology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000145:classification / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D021122:Protein Subunits; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000502:physiology*; D000077191:Wortmannin
D000730:Androstadienes; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D019000:Phosphotyrosine; D021122:Protein Subunits; D000077191:Wortmannin