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 ho st phosphatidylinositol (PI) S-kinases during T. cruzi invasion. The PI 3-k inase inhibitor wortmannin marked inhibited T. cruzi infection when macroph ages were pretreated for 20 min at 37 degrees C before inoculation. Infecti on of macrophages with T. cruzi markedly stimulated the formation of the li pid 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 act ivities that are present in the immunoprecipitates of anti-p85 subunit of c lass 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 invasio n into macrophages strongly activates separated PI 3-kinase isoforms. Furth ermore, the inhibition of the class I and class III PI 3-kinase activities abolishes the parasite entry into macrophages. These findings suggest a pro minent role for the host PI 3-kinase activities during the T. cruzi infecti on process.