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The glycosylphosphatidylinositol (GPI) anchors of Plasmodium falciparum have been proposed to be the major factors that contribute to malaria pathogenesis through their ability to induce proinflammatory responses. In this study we identified the receptors for P. falciparum GPI-induced cell signaling that leads to proinflammatory responses and studied the GPI structure-activity relationship. The data show that GPI signaling is mediated mainly through recognition by TLR2 and to a lesser extent by TLR4. The activity of sn-2-lyso-GPIs is comparable with that of the intact GPIs, whereas the activity of Man3-GPIs is about 80% that of the intact GPIs. The GPIs with three (intact GPIs and Man3-GPIs) and two fatty acids (sn-2-lyso-GPIs) appear to differ considerably in the requirement of the auxiliary receptor, TLR1 or TLR6, for recognition by TLR2. The former are preferentially recognized by TLR2/TLR1, whereas the latter are favored by TLR2/TLR6. However, the signaling pathways initiated by all three GPI types are similar, involving the MyD88-dependent activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 and NF-κB-signaling pathways. The signaling molecules of these pathways differentially contribute to the production of various cytokines and nitric oxide (Zhu, J., Krishnegowda, G., and Gowda, D. C. (2004) J. Biol. Chem. 280, 8617-8627). Our data also show that GPIs are degraded by the macrophage surface phospholipases predominantly into inactive species, indicating that the host can regulate GPI activity at least in part by this mechanism. These results imply that macrophage surface phospholipases play important roles in the GPI-induced innate immune responses and malaria pathogenesis. The glycosylphosphatidylinositol (GPI) anchors of Plasmodium falciparum have been proposed to be the major factors that contribute to malaria pathogenesis through their ability to induce proinflammatory responses. In this study we identified the receptors for P. falciparum GPI-induced cell signaling that leads to proinflammatory responses and studied the GPI structure-activity relationship. The data show that GPI signaling is mediated mainly through recognition by TLR2 and to a lesser extent by TLR4. The activity of sn-2-lyso-GPIs is comparable with that of the intact GPIs, whereas the activity of Man3-GPIs is about 80% that of the intact GPIs. The GPIs with three (intact GPIs and Man3-GPIs) and two fatty acids (sn-2-lyso-GPIs) appear to differ considerably in the requirement of the auxiliary receptor, TLR1 or TLR6, for recognition by TLR2. The former are preferentially recognized by TLR2/TLR1, whereas the latter are favored by TLR2/TLR6. However, the signaling pathways initiated by all three GPI types are similar, involving the MyD88-dependent activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 and NF-κB-signaling pathways. The signaling molecules of these pathways differentially contribute to the production of various cytokines and nitric oxide (Zhu, J., Krishnegowda, G., and Gowda, D. C. (2004) J. Biol. Chem. 280, 8617-8627). Our data also show that GPIs are degraded by the macrophage surface phospholipases predominantly into inactive species, indicating that the host can regulate GPI activity at least in part by this mechanism. These results imply that macrophage surface phospholipases play important roles in the GPI-induced innate immune responses and malaria pathogenesis. Malaria caused by the parasitic protozoa of the genus Plasmodium is a major public health problem in Africa, South America, and South Asia (1Gilles H.M. Warrell D.A. Bruce-Chawatt's Essential Malariology. Arnold Publishers, London1997: 1-340Google Scholar, 2Sherman I.W. Malaria: Parasite Biology, Pathogenesis, and Protection. American Society for Microbiology, Washington, D. C.1998: 1-575Google Scholar, 3Snow R.W. Craig M.H. Deichmann U. Marsh K. Bull. W. H. O. 1999; 77: 624-640PubMed Google Scholar, 4Sachs J. Malaney P. Nature. 2002; 415: 680-685Crossref PubMed Scopus (1411) Google Scholar). The disease afflicts about 500 million people and causes ∼3 million deaths annually and ranks first among the various infectious diseases, causing global morbidity and mortality. More than 100 Plasmodium species exist in nature that can infect various vertebrate animals (1Gilles H.M. Warrell D.A. Bruce-Chawatt's Essential Malariology. Arnold Publishers, London1997: 1-340Google Scholar). However, only four species are infectious to man, and of these, Plasmodium falciparum is responsible for >95% of deaths (1Gilles H.M. Warrell D.A. Bruce-Chawatt's Essential Malariology. Arnold Publishers, London1997: 1-340Google Scholar, 2Sherman I.W. Malaria: Parasite Biology, Pathogenesis, and Protection. American Society for Microbiology, Washington, D. C.1998: 1-575Google Scholar, 3Snow R.W. Craig M.H. Deichmann U. Marsh K. Bull. W. H. O. 1999; 77: 624-640PubMed Google Scholar, 4Sachs J. Malaney P. Nature. 2002; 415: 680-685Crossref PubMed Scopus (1411) Google Scholar). Plasmodium infection causes a wide range of clinical manifestations, including cerebral malaria, acute respiratory distress, pulmonary edema, renal failure, and severe anemia (1Gilles H.M. Warrell D.A. Bruce-Chawatt's Essential Malariology. Arnold Publishers, London1997: 1-340Google Scholar, 2Sherman I.W. Malaria: Parasite Biology, Pathogenesis, and Protection. American Society for Microbiology, Washington, D. C.1998: 1-575Google Scholar). The acquisition of effective protective immunity to malaria requires repetitive infections over a period of a few years (5Baird J.K. Parasitol. 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Scopus Google Scholar). The results of this study that cell surface phospholipases regulate the activity of GPIs. Our results show that the P. falciparum GPIs to are degraded by the cell surface or including and D. to in with or the of the GPIs to by the of D. the of are to the production of proinflammatory data that regulate the activity of GPIs at least in part by into inactive The of GPI activity is to be in in the of and and GPIs are be of the by the host immune activity that is in to GPIs. have the of innate immune to P. falciparum GPIs and the ability of host to the GPI activity during These have important in host and the of pathogenesis. of Washington, for and
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