Abstract
Host resistance to the intracellular protozoan Toxoplasma gondii is highly dependent on early IL-12 production by APC. We demonstrate here that both host resistance and T. gondii-induced IL-12 production are dramatically reduced in mice lacking the adaptor molecule MyD88, an important signaling element used by Toll-like receptor (TLR) family members. Infection of MyD88-deficient mice with T. gondii resulted in uncontrolled parasite replication and greatly reduced plasma IL-12 levels. Defective IL-12 responses to T. gondii Ags (soluble tachyzoite Ag (STAg)) were observed in MyD88(-/-) peritoneal macrophages, neutrophils, and splenic dendritic cells (DC). In contrast, DC from TLR2- or TLR4-deficient animals developed normal IL-12 responses to STAg. In vivo treatment with pertussis toxin abolished the residual IL-12 response displayed by STAg-stimulated DC from MyD88(-/-) mice. Taken together, these data suggest that the induction of IL-12 by T. gondii depends on a unique mechanism involving both MyD88 and G protein-coupled signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
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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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Dendritic Cells / parasitology
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Drosophila Proteins*
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Female
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Immunity, Innate / genetics
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Interferon-gamma / biosynthesis
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Interferon-gamma / deficiency
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Interleukin-12 / biosynthesis*
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Interleukin-12 / deficiency
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Macrophages, Peritoneal / parasitology
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Male
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / physiology
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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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Neutrophils / immunology
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Neutrophils / metabolism
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Neutrophils / parasitology
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Receptors, CCR5 / physiology
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Receptors, Cell Surface / deficiency
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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 / immunology
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptors
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Toxoplasma / immunology*
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Toxoplasmosis, Animal / genetics
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Toxoplasmosis, Animal / immunology*
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Toxoplasmosis, Animal / mortality
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Toxoplasmosis, Animal / parasitology*
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Drosophila Proteins
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, CCR5
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Receptors, Cell Surface
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Receptors, Immunologic
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptors
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Interleukin-12
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Interferon-gamma