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• W2070264872 abstract "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. cruziinvasion. The PI 3-kinase inhibitor wortmannin marked inhibitedT. cruzi infection when macrophages were pretreated for 20 min at 37 °C before inoculation. Infection of macrophages withT. 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 thatT. 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. 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. cruziinvasion. The PI 3-kinase inhibitor wortmannin marked inhibitedT. cruzi infection when macrophages were pretreated for 20 min at 37 °C before inoculation. Infection of macrophages withT. 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 thatT. 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. phosphatidylinositol Dulbecco's modified Eagle's medium DMEM supplemented with fetal bovine serum high performance liquid chromatography Trypanosoma cruzi, an intracellular protozoan parasite that infects humans and other mammalian hosts, is the etiologic agent of Chagas' disease that is a major public health problem in Latin America (1World Health Organization Weekly Epidemiol. Rec. 1997; 1: 1-8Google Scholar). This parasite is now viewed as an emerging human pathogen of HIV-1-infected individuals as it can be transmitted through blood transfusions (2National Institute of Allergy and Infectious Diseases Council News. 1996; 5: 1-16Google Scholar). This unicellular parasite presents three developmental stages; epimastigote and amastigote forms correspond to proliferative stages found in the invertebrate and vertebrate hosts, respectively. The trypomastigote forms are infective and invade different host cell types, first macrophages, in order to replicate (3Burleigh B.A. Andrews N.W. Annu. Rev. Microbiol. 1995; 49: 175-200Crossref PubMed Scopus (190) Google Scholar).How T. cruzi trypomastigotes signal to gain entry and survive in their host is not completely understood. However, some evidence suggests that T. cruzi interacts with different signaling systems of the host. It has been shown that the transforming growth factor β-receptor signaling pathway is essential for T. cruzi invasion (4Ming M. Ewen M.E. Pereira M.E. Cell. 1995; 82: 287-296Abstract Full Text PDF PubMed Scopus (136) Google Scholar). Activation of a calcium-dependent host cell pathway by T. cruzihas also been reported (3Burleigh B.A. Andrews N.W. Annu. Rev. Microbiol. 1995; 49: 175-200Crossref PubMed Scopus (190) Google Scholar, 5Moreno S.N.J. Silva J. Vercesi A.E. Docampo R. J. Exp. Med. 1994; 180: 1535-1540Crossref PubMed Scopus (181) Google Scholar). In addition, T. cruziinvasion has been shown to induce tyrosine phosphorylation of macrophage proteins (6Ruta S. Plasman N. Zaffran Y. Capo C. Mege J.L. Vray B. Parasitol. Res. 1996; 82: 481-484Crossref PubMed Scopus (11) Google Scholar), as well as activation of the mitogen-activated protein kinase pathway (7Villalta F. Zhang Y. Bibb K.E. Burns Jr., J.M. Lima M.F. Biochem. Biophys. Res. Commun. 1998; 249: 247-252Crossref PubMed Scopus (37) Google Scholar). Thus, the blockade of tyrosine kinase and mitogen-activated protein kinase activities in the host macrophage by inhibitors (7Villalta F. Zhang Y. Bibb K.E. Burns Jr., J.M. Lima M.F. Biochem. Biophys. Res. Commun. 1998; 249: 247-252Crossref PubMed Scopus (37) Google Scholar, 8Vieira M.C. Carvalho T.U. De Souza W. Biochem. Biophys. Res. Commun. 1994; 203: 967-971Crossref PubMed Scopus (45) Google Scholar) ablate the infection of these cells byT. cruzi, suggesting that activation of kinase pathways is an important event in this process. Invasion of T. cruzi into cells also appears to trigger an unusual mechanism, which involves recruitment and fusion of host lysosomes at the invasion site (3Burleigh B.A. Andrews N.W. Annu. Rev. Microbiol. 1995; 49: 175-200Crossref PubMed Scopus (190) Google Scholar), suggesting that this parasite is able to interact with host signaling systems that regulate membrane trafficking.Several forms of evidence now indicate that phosphorylation of the D-3 position of the inositol ring of phosphoinositides, catalyzed by phosphatidylinositol (PI)13-kinases, is a critical step in many cellular processes, such as cytoskeletal rearrangement, membrane trafficking, and endosome fusion (9Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1218) Google Scholar, 10Corvera S. Czech M.P. Trends Cell Biol. 1998; 8: 442-446Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). Thus, tyrosine phosphorylation of proteins containing YXXM motifs creates docking sites for Src homology 2 domains that are present on the p85 regulatory subunits of class I PI 3-kinase, p85/p110-type (9Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1218) Google Scholar). The binding of p85 to these tyrosine-phosphorylated proteins activates the associated p110 catalytic subunit of PI 3-kinase, which catalyzes the phosphorylation of PI 4,5-P2 to PI 3,4,5-P3. The class II PI 3-kinases represent a novel group of PI 3-kinases containing a C2 domain at their C terminus, and three mammalian isoforms, namely PI 3-kinase C2α, PI 3-kinase C2β, and PI 3-kinase C2γ, have been cloned (11Virbasius J.V. Guilherme A. Czech M.P. J. Biol. Chem. 1996; 271: 13304-13307Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 12Arcaro A. Volinia S. Zvelebil M.J. Stein R. Watton S.J. Layton M.J. Gout I. Ahmadi K. Downward J. Waterfield M.D. J. Biol. Chem. 1998; 273: 33082-33090Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 13Ono F. Nakagawa T. Saito S. Owada Y. Sakagami H. Goto K. Suzuki M. Matsuno S. Kondo H. J. Biol. Chem. 1998; 273: 7731-7736Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). These PI 3-kinases prefer to phosphorylate PI and PI 4-P as substrates in vitro, but not PI 4,5-P2. The role of class II PI 3-kinases in the cells and their regulations are not understood, although some recent reports show activation of class II PI 3-kinases by chemokine MCP-1 (monocyte chemoattractant protein) in monocytes (14Turner S.J. Domin J. Waterfield M.D. Ward S.G. Westwick J. J. Biol. Chem. 1998; 273: 25987-25995Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar), by platelet aggregation (15Zhang J. Banfic H. Straforini F. Tosi L. Volinia S. Rittenhouse S.E. J. Biol. Chem. 1998; 273: 14081-14084Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), and by insulin-mediated protein phosphorylation (16Brown R.A. Domin I. Arcaro A. Waterfield M.D. Shepherd P.R. J. Biol. Chem. 1999; 274: 14529-14532Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Class III enzymes are homologous to the archetypal Vps34p characterized inSaccharomyces cerevisiae, which only produce PI 3-P (17Schu P.V. Takegawa K. Fry M.J. Stack J.H. Waterfield M.D. Emr S.D. Science. 1993; 260: 88-91Crossref PubMed Scopus (803) Google Scholar). Vps34p function requires its association with myristoylated serine kinase Vps15p (18Vanhaesebroeck B. Waterfield M.D. Exp. Cell Res. 1999; 253: 239-254Crossref PubMed Scopus (758) Google Scholar). The complex Vps15p-Vps34p is of fundamental importance in controlling vesicular transport to the yeast vacuole (reviewed in Ref. 19Wurmser A.E. Gary J.D. Emr S.D. J. Biol. Chem. 1999; 274: 9129-9132Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar).Some of the downstream elements that mediate the action of lipid products of PI 3-kinases appear to include: 1) serine/threonine kinases PKB and PDK-1 (9Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1218) Google Scholar, 20Stokoe D. Stephens L.R. Copeland T. Gaffney P.R. Reese C.B. Painter G.F. Holmes A.B. McCormick F. Hawkins P.T. Science. 1997; 277: 567-570Crossref PubMed Scopus (1045) Google Scholar) and a non-receptor tyrosine kinase Tec family, which binds PI 3,4,5,-P3 and elicits Ca2+-dependent signaling events (21Scharenberg A.M. Kinet J.P. Cell. 1998; 94: 5-8Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar); 2) a family of PI 3,4,5-P3-binding proteins that contains guanine nucleotide exchange activity for ADP-ribosylation factors and that is potentially involved in membrane trafficking (22Klarlund J. Guilherme A. Holik J.J. Virbasius J.V. Chawla A. Czech M.P. Science. 1997; 275: 1927-1930Crossref PubMed Scopus (368) Google Scholar, 23Frank S. Upender S. Hansen S.H. Casanova J.E. J. Biol. Chem. 1998; 273: 23-27Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar); and 3) a FYVE RING domain containing protein EEA-1, which binds PI 3-P and Rab5 and appears to be required for endosome fusion in vitro (10Corvera S. Czech M.P. Trends Cell Biol. 1998; 8: 442-446Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 24Simonsen A. Lippe R. Christoforidis S. Gaullier J.M. Brech A. Callaghan J. Toh B.H. Murphy C. Zerial M. Stenmark H. Nature. 1998; 394: 494-498Crossref PubMed Scopus (908) Google Scholar). Thus, PI 3-kinase activity appears to influence a multiplicity of cell functions.A key role for host cell tyrosine phosphorylation and activation of class I PI 3-kinase in bacteria Listeria monocytogenes (25Ireton K. Payrastre B. Chap H. Ogawa W. Sakaue H. Kasuga M. Cossart P. Science. 1996; 274: 780-782Crossref PubMed Scopus (287) Google Scholar) and in protozoan, Cryptosporidium parvum (26Forney J.R. DeWald D.B. Yang S. Speer A.C. Healey M.C. Infect. Immun. 1999; 67: 844-852Crossref PubMed Google Scholar) cell invasion has been shown. However, the effect of T. cruziinvasion on the host lipid kinases has not been studied. In the present studies, we address the question of whether T. cruziinfection may activate host cell PI 3-kinases and if efficient infection requires the host PI 3-kinase activity. Here we show thatT. cruzi infection causes marked increases in cellular amounts of PI 3-P, PI 3,4-P2, and PI 3,4,5-P3, as well as host PI 3-kinase activation. Moreover, the PI 3-kinase inhibitor wortmannin strongly blocked T. cruzi infection. These results suggest an important role for host PI 3-kinases in theT. cruzi infection process. Trypanosoma cruzi, an intracellular protozoan parasite that infects humans and other mammalian hosts, is the etiologic agent of Chagas' disease that is a major public health problem in Latin America (1World Health Organization Weekly Epidemiol. Rec. 1997; 1: 1-8Google Scholar). This parasite is now viewed as an emerging human pathogen of HIV-1-infected individuals as it can be transmitted through blood transfusions (2National Institute of Allergy and Infectious Diseases Council News. 1996; 5: 1-16Google Scholar). This unicellular parasite presents three developmental stages; epimastigote and amastigote forms correspond to proliferative stages found in the invertebrate and vertebrate hosts, respectively. The trypomastigote forms are infective and invade different host cell types, first macrophages, in order to replicate (3Burleigh B.A. Andrews N.W. Annu. Rev. Microbiol. 1995; 49: 175-200Crossref PubMed Scopus (190) Google Scholar). How T. cruzi trypomastigotes signal to gain entry and survive in their host is not completely understood. However, some evidence suggests that T. cruzi interacts with different signaling systems of the host. It has been shown that the transforming growth factor β-receptor signaling pathway is essential for T. cruzi invasion (4Ming M. Ewen M.E. Pereira M.E. Cell. 1995; 82: 287-296Abstract Full Text PDF PubMed Scopus (136) Google Scholar). Activation of a calcium-dependent host cell pathway by T. cruzihas also been reported (3Burleigh B.A. Andrews N.W. Annu. Rev. Microbiol. 1995; 49: 175-200Crossref PubMed Scopus (190) Google Scholar, 5Moreno S.N.J. Silva J. Vercesi A.E. Docampo R. J. Exp. Med. 1994; 180: 1535-1540Crossref PubMed Scopus (181) Google Scholar). In addition, T. cruziinvasion has been shown to induce tyrosine phosphorylation of macrophage proteins (6Ruta S. Plasman N. Zaffran Y. Capo C. Mege J.L. Vray B. Parasitol. Res. 1996; 82: 481-484Crossref PubMed Scopus (11) Google Scholar), as well as activation of the mitogen-activated protein kinase pathway (7Villalta F. Zhang Y. Bibb K.E. Burns Jr., J.M. Lima M.F. Biochem. Biophys. Res. Commun. 1998; 249: 247-252Crossref PubMed Scopus (37) Google Scholar). Thus, the blockade of tyrosine kinase and mitogen-activated protein kinase activities in the host macrophage by inhibitors (7Villalta F. Zhang Y. Bibb K.E. Burns Jr., J.M. Lima M.F. Biochem. Biophys. Res. Commun. 1998; 249: 247-252Crossref PubMed Scopus (37) Google Scholar, 8Vieira M.C. Carvalho T.U. De Souza W. Biochem. Biophys. Res. Commun. 1994; 203: 967-971Crossref PubMed Scopus (45) Google Scholar) ablate the infection of these cells byT. cruzi, suggesting that activation of kinase pathways is an important event in this process. Invasion of T. cruzi into cells also appears to trigger an unusual mechanism, which involves recruitment and fusion of host lysosomes at the invasion site (3Burleigh B.A. Andrews N.W. Annu. Rev. Microbiol. 1995; 49: 175-200Crossref PubMed Scopus (190) Google Scholar), suggesting that this parasite is able to interact with host signaling systems that regulate membrane trafficking. Several forms of evidence now indicate that phosphorylation of the D-3 position of the inositol ring of phosphoinositides, catalyzed by phosphatidylinositol (PI)13-kinases, is a critical step in many cellular processes, such as cytoskeletal rearrangement, membrane trafficking, and endosome fusion (9Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1218) Google Scholar, 10Corvera S. Czech M.P. Trends Cell Biol. 1998; 8: 442-446Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). Thus, tyrosine phosphorylation of proteins containing YXXM motifs creates docking sites for Src homology 2 domains that are present on the p85 regulatory subunits of class I PI 3-kinase, p85/p110-type (9Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1218) Google Scholar). The binding of p85 to these tyrosine-phosphorylated proteins activates the associated p110 catalytic subunit of PI 3-kinase, which catalyzes the phosphorylation of PI 4,5-P2 to PI 3,4,5-P3. The class II PI 3-kinases represent a novel group of PI 3-kinases containing a C2 domain at their C terminus, and three mammalian isoforms, namely PI 3-kinase C2α, PI 3-kinase C2β, and PI 3-kinase C2γ, have been cloned (11Virbasius J.V. Guilherme A. Czech M.P. J. Biol. Chem. 1996; 271: 13304-13307Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 12Arcaro A. Volinia S. Zvelebil M.J. Stein R. Watton S.J. Layton M.J. Gout I. Ahmadi K. Downward J. Waterfield M.D. J. Biol. Chem. 1998; 273: 33082-33090Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 13Ono F. Nakagawa T. Saito S. Owada Y. Sakagami H. Goto K. Suzuki M. Matsuno S. Kondo H. J. Biol. Chem. 1998; 273: 7731-7736Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). These PI 3-kinases prefer to phosphorylate PI and PI 4-P as substrates in vitro, but not PI 4,5-P2. The role of class II PI 3-kinases in the cells and their regulations are not understood, although some recent reports show activation of class II PI 3-kinases by chemokine MCP-1 (monocyte chemoattractant protein) in monocytes (14Turner S.J. Domin J. Waterfield M.D. Ward S.G. Westwick J. J. Biol. Chem. 1998; 273: 25987-25995Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar), by platelet aggregation (15Zhang J. Banfic H. Straforini F. Tosi L. Volinia S. Rittenhouse S.E. J. Biol. Chem. 1998; 273: 14081-14084Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), and by insulin-mediated protein phosphorylation (16Brown R.A. Domin I. Arcaro A. Waterfield M.D. Shepherd P.R. J. Biol. Chem. 1999; 274: 14529-14532Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Class III enzymes are homologous to the archetypal Vps34p characterized inSaccharomyces cerevisiae, which only produce PI 3-P (17Schu P.V. Takegawa K. Fry M.J. Stack J.H. Waterfield M.D. Emr S.D. Science. 1993; 260: 88-91Crossref PubMed Scopus (803) Google Scholar). Vps34p function requires its association with myristoylated serine kinase Vps15p (18Vanhaesebroeck B. Waterfield M.D. Exp. Cell Res. 1999; 253: 239-254Crossref PubMed Scopus (758) Google Scholar). The complex Vps15p-Vps34p is of fundamental importance in controlling vesicular transport to the yeast vacuole (reviewed in Ref. 19Wurmser A.E. Gary J.D. Emr S.D. J. Biol. Chem. 1999; 274: 9129-9132Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). Some of the downstream elements that mediate the action of lipid products of PI 3-kinases appear to include: 1) serine/threonine kinases PKB and PDK-1 (9Toker A. Cantley L.C. Nature. 1997; 387: 673-676Crossref PubMed Scopus (1218) Google Scholar, 20Stokoe D. Stephens L.R. Copeland T. Gaffney P.R. Reese C.B. Painter G.F. Holmes A.B. McCormick F. Hawkins P.T. Science. 1997; 277: 567-570Crossref PubMed Scopus (1045) Google Scholar) and a non-receptor tyrosine kinase Tec family, which binds PI 3,4,5,-P3 and elicits Ca2+-dependent signaling events (21Scharenberg A.M. Kinet J.P. Cell. 1998; 94: 5-8Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar); 2) a family of PI 3,4,5-P3-binding proteins that contains guanine nucleotide exchange activity for ADP-ribosylation factors and that is potentially involved in membrane trafficking (22Klarlund J. Guilherme A. Holik J.J. Virbasius J.V. Chawla A. Czech M.P. Science. 1997; 275: 1927-1930Crossref PubMed Scopus (368) Google Scholar, 23Frank S. Upender S. Hansen S.H. Casanova J.E. J. Biol. Chem. 1998; 273: 23-27Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar); and 3) a FYVE RING domain containing protein EEA-1, which binds PI 3-P and Rab5 and appears to be required for endosome fusion in vitro (10Corvera S. Czech M.P. Trends Cell Biol. 1998; 8: 442-446Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 24Simonsen A. Lippe R. Christoforidis S. Gaullier J.M. Brech A. Callaghan J. Toh B.H. Murphy C. Zerial M. Stenmark H. Nature. 1998; 394: 494-498Crossref PubMed Scopus (908) Google Scholar). Thus, PI 3-kinase activity appears to influence a multiplicity of cell functions. A key role for host cell tyrosine phosphorylation and activation of class I PI 3-kinase in bacteria Listeria monocytogenes (25Ireton K. Payrastre B. Chap H. Ogawa W. Sakaue H. Kasuga M. Cossart P. Science. 1996; 274: 780-782Crossref PubMed Scopus (287) Google Scholar) and in protozoan, Cryptosporidium parvum (26Forney J.R. DeWald D.B. Yang S. Speer A.C. Healey M.C. Infect. Immun. 1999; 67: 844-852Crossref PubMed Google Scholar) cell invasion has been shown. However, the effect of T. cruziinvasion on the host lipid kinases has not been studied. In the present studies, we address the question of whether T. cruziinfection may activate host cell PI 3-kinases and if efficient infection requires the host PI 3-kinase activity. Here we show thatT. cruzi infection causes marked increases in cellular amounts of PI 3-P, PI 3,4-P2, and PI 3,4,5-P3, as well as host PI 3-kinase activation. Moreover, the PI 3-kinase inhibitor wortmannin strongly blocked T. cruzi infection. These results suggest an important role for host PI 3-kinases in theT. cruzi infection process. We thank Dr. Joseph V. Virbasius and Dr. Michael P. Czech for the gifts of anti-PI 3-kinase C2α and anti-class III PI 3-kinase polyclonal antibodies." @default.
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• W2070264872 title "Activation of Host Cell Phosphatidylinositol 3-Kinases byTrypanosoma cruzi Infection" @default.
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