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*
Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais and Centro de Pesquisas René Rachou, Oswaldo Cruz Foundation, Belo Horizonte, Brazil;
Department of Parasitology, University of Sao Paulo, Sao Paulo, Brazil;
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;
Unit for Experimental Oncology, Federal University of Sao Paulo, Sao Paulo, Brazil; and
¶ Boston University School of Medicine, Boston, MA 02118
Glycosylphosphatidylinositol (GPI) anchors and
glycoinositolphospholipids (GIPLs) from parasitic protozoa have been
shown to exert a wide variety of effects on cells of the host innate
immune system. However, the receptor(s) that are triggered by these
protozoan glycolipids has not been identified. Here we present evidence
that Trypanosoma cruzi-derived GPI anchors and GIPLs
trigger CD25 expression on Chinese hamster ovary-K1 cells transfected
with CD14 and Toll-like receptor-2 (TLR-2), but not wild-type
(TLR-2-deficient) Chinese hamster ovary cells. The protozoan-derived
GPI anchors and GIPLs containing alkylacylglycerol and saturated
fatty acid chains or ceramide were found to be active in a
concentration range of 100 nM to 1 µM. More importantly, the GPI
anchors purified from T. cruzi trypomastigotes, which
contain a longer glycan core and unsaturated fatty acids in the sn-2
position of the alkylacylglycerolipid component, triggered TLR-2 at
subnanomolar concentrations. We performed experiments with macrophages
from TLR-2 knockout and TLR-4 knockout mice, and found that TLR-2
expression appears to be essential for induction of IL-12, TNF-
, and
NO by GPI anchors derived from T. cruzi trypomastigotes.
Thus, highly purified GPI anchors from T. cruzi
parasites are potent activators of TLR-2 from both mouse and human
origin. The activation of TLR-2 may initiate host innate defense
mechanisms and inflammatory response during protozoan infection, and
may provide new strategies for immune intervention during protozoan
infections.
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C. Ropert, M. Closel, A. C. L. Chaves, and R. T. Gazzinelli Inhibition of a p38/Stress-Activated Protein Kinase-2-Dependent Phosphatase Restores Function of IL-1 Receptor-Associated Kinase-1 and Reverses Toll-Like Receptor 2- and 4-Dependent Tolerance of Macrophages J. Immunol., August 1, 2003; 171(3): 1456 - 1465. [Abstract] [Full Text] [PDF]
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C. S. Boutlis, E. Tjitra, H. Maniboey, M. A. Misukonis, J. R. Saunders, S. Suprianto, J. B. Weinberg, and N. M. Anstey Nitric Oxide Production and Mononuclear Cell Nitric Oxide Synthase Activity in Malaria-Tolerant Papuan Adults Infect. Immun., July 1, 2003; 71(7): 3682 - 3689. [Abstract] [Full Text] [PDF]
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N. Delgado, J. Xue, J.-J. Yu, C.-Y. Hung, and G. T. Cole A Recombinant {beta}-1,3-Glucanosyltransferase Homolog of Coccidioides posadasii Protects Mice against Coccidioidomycosis Infect. Immun., June 1, 2003; 71(6): 3010 - 3019. [Abstract] [Full Text] [PDF]
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 N. L. Bernasconi, N. Onai, and A. Lanzavecchia A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells Blood, June 1, 2003; 101(11): 4500 - 4504. [Abstract] [Full Text] [PDF]
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T. K. Means, F. Hayashi, K. D. Smith, A. Aderem, and A. D. Luster The Toll-Like Receptor 5 Stimulus Bacterial Flagellin Induces Maturation and Chemokine Production in Human Dendritic Cells J. Immunol., May 15, 2003; 170(10): 5165 - 5175. [Abstract] [Full Text] [PDF]
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 A. Dunne and L. A. J. O'Neill The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense Sci. Signal., February 25, 2003; 2003(171): re3 - re3. [Abstract] [Full Text] [PDF]
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L. R. P. Ferreira, E. F. Abrantes, C. V. Rodrigues, B. Caetano, G. C. Cerqueira, A. C. Salim, L. F. L. Reis, and R. T. Gazzinelli Identification and characterization of a novel mouse gene encoding a Ras-associated guanine nucleotide exchange factor: expression in macrophages and myocarditis elicited by Trypanosoma cruzi parasites J. Leukoc. Biol., December 1, 2002; 72(6): 1215 - 1227. [Abstract] [Full Text] [PDF]
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D. O. Procopio, I. C. Almeida, A. C. T. Torrecilhas, J. E. Cardoso, L. Teyton, L. R. Travassos, A. Bendelac, and R. T. Gazzinelli Glycosylphosphatidylinositol-Anchored Mucin-Like Glycoproteins from Trypanosoma cruzi Bind to CD1d but Do Not Elicit Dominant Innate or Adaptive Immune Responses Via the CD1d/NKT Cell Pathway J. Immunol., October 1, 2002; 169(7): 3926 - 3933. [Abstract] [Full Text] [PDF]
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K. Artavanis-Tsakonas and E. M. Riley Innate Immune Response to Malaria: Rapid Induction of IFN-{gamma} from Human NK Cells by Live Plasmodium falciparum-Infected Erythrocytes J. Immunol., September 15, 2002; 169(6): 2956 - 2963. [Abstract] [Full Text] [PDF]
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J. B. de Souza, J. Todd, G. Krishegowda, D. C. Gowda, D. Kwiatkowski, and E. M. Riley Prevalence and Boosting of Antibodies to Plasmodium falciparum Glycosylphosphatidylinositols and Evaluation of Their Association with Protection from Mild and Severe Clinical Malaria Infect. Immun., September 1, 2002; 70(9): 5045 - 5051. [Abstract] [Full Text] [PDF]
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 S. E. Applequist, R. P. A. Wallin, and H.-G. Ljunggren Variable expression of Toll-like receptor in murine innate and adaptive immune cell lines Int. Immunol., September 1, 2002; 14(9): 1065 - 1074. [Abstract] [Full Text] [PDF]
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J. Caamano and C. A. Hunter NF-{kappa}B Family of Transcription Factors: Central Regulators of Innate and Adaptive Immune Functions Clin. Microbiol. Rev., July 1, 2002; 15(3): 414 - 429. [Abstract] [Full Text] [PDF]
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C. Brodskyn, J. Patricio, R. Oliveira, L. Lobo, A. Arnholdt, L. Mendonca-Previato, A. Barral, and M. Barral-Netto Glycoinositolphospholipids from Trypanosoma cruzi Interfere with Macrophages and Dendritic Cell Responses Infect. Immun., July 1, 2002; 70(7): 3736 - 3743. [Abstract] [Full Text] [PDF]
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O. Takeuchi, S. Sato, T. Horiuchi, K. Hoshino, K. Takeda, Z. Dong, R. L. Modlin, and S. Akira Cutting Edge: Role of Toll-Like Receptor 1 in Mediating Immune Response to Microbial Lipoproteins J. Immunol., July 1, 2002; 169(1): 10 - 14. [Abstract] [Full Text] [PDF]
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C. A. Scanga, J. Aliberti, D. Jankovic, F. Tilloy, S. Bennouna, E. Y. Denkers, R. Medzhitov, and A. Sher Cutting Edge: MyD88 Is Required for Resistance to Toxoplasma gondii Infection and Regulates Parasite-Induced IL-12 Production by Dendritic Cells J. Immunol., June 15, 2002; 168(12): 5997 - 6001. [Abstract] [Full Text] [PDF]
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A. Ouaissi, E. Guilvard, Y. Delneste, G. Caron, G. Magistrelli, N. Herbault, N. Thieblemont, and P. Jeannin The Trypanosoma cruzi Tc52-Released Protein Induces Human Dendritic Cell Maturation, Signals Via Toll-Like Receptor 2, and Confers Protection Against Lethal Infection J. Immunol., June 15, 2002; 168(12): 6366 - 6374. [Abstract] [Full Text] [PDF]
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P. S. Coelho, A. Klein, A. Talvani, S. F. Coutinho, O. Takeuchi, S. Akira, J. S. Silva, H. Canizzaro, R. T. Gazzinelli, and M. M. Teixeira Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzi trypomastigotes induce in vivo leukocyte recruitment dependent on MCP-1 production by IFN-{gamma}-primed-macrophages J. Leukoc. Biol., May 1, 2002; 71(5): 837 - 844. [Abstract] [Full Text] [PDF]
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A. Fox-Marsh and L. C. Harrison Emerging evidence that molecules expressed by mammalian tissue grafts are recognized by the innate immune system J. Leukoc. Biol., March 1, 2002; 71(3): 401 - 409. [Abstract] [Full Text] [PDF]
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K. Adachi, H. Tsutsui, S.-I. Kashiwamura, E. Seki, H. Nakano, O. Takeuchi, K. Takeda, K. Okumura, L. Van Kaer, H. Okamura, et al. Plasmodiumberghei Infection in Mice Induces Liver Injury by an IL-12- and Toll-Like Receptor/Myeloid Differentiation Factor 88-Dependent Mechanism J. Immunol., November 15, 2001; 167(10): 5928 - 5934. [Abstract] [Full Text] [PDF]
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I. C. Almeida and R. T. Gazzinelli Proinflammatory activity of glycosylphosphatidylinositol anchors derived from Trypanosoma cruzi: structural and functional analyses J. Leukoc. Biol., October 1, 2001; 70(4): 467 - 477. [Abstract] [Full Text] [PDF]
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