Abstract
A common feature of severe Plasmodium falciparum infection is the increased systemic release of proinflammatory cytokines that contributes to the pathogenesis of malaria. Using human blood, we found that blood stage schizonts or soluble schizont extracts activated plasmacytoid dendritic cells (PDCs) to up-regulate CD86 expression and produce IFN-alpha. IFN-alpha production was also detected in malaria-infected patients, but the levels of circulating PDCs were markedly reduced, possibly because of schizont-stimulated up-regulation of CCR7, which is critical for PDC migration. The schizont-stimulated PDCs elicited a poor T cell response, but promoted gamma delta T cell proliferation and IFN-gamma production. The schizont immune stimulatory effects could be reproduced using murine DCs and required the Toll-like receptor 9 (TLR9)-MyD88 signaling pathway. Although the only known TLR9 ligand is CpG motifs in pathogen DNA, the activity of the soluble schizont extract was far greater than that of schizont DNA, and it was heat labile and precipitable with ammonium sulfate, unlike the activity of bacterial DNA. These results demonstrate that schizont extracts contain a novel and previously unknown ligand for TLR9 and suggest that the stimulatory effects of this ligand on PDCs may play a key role in immunoregulation and immunopathogenesis of human falciparum malaria.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / physiology
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Cell Fractionation
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Cell Movement / immunology
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Cells, Cultured
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Coculture Techniques
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / parasitology*
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Dendritic Cells / pathology
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Humans
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Immunity, Cellular
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Interferon-alpha / biosynthesis
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Interferon-alpha / blood
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Malaria, Falciparum / blood
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Malaria, Falciparum / immunology*
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Malaria, Falciparum / parasitology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88
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Plasmodium falciparum / chemistry
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Plasmodium falciparum / growth & development*
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Plasmodium falciparum / immunology*
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Receptors, Antigen, T-Cell, gamma-delta / biosynthesis
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / physiology*
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Receptors, Immunologic / deficiency
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Solubility
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / parasitology
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Toll-Like Receptor 9
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Up-Regulation / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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DNA-Binding Proteins
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Interferon-alpha
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MYD88 protein, human
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Antigen, T-Cell, gamma-delta
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Receptors, Cell Surface
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Receptors, Immunologic
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TLR9 protein, human
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Tlr9 protein, mouse
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Toll-Like Receptor 9