Abstract
Activation of innate immune cells by Trypanosoma cruzi-derived molecules such as GPI anchors and DNA induces proinflammatory cytokine production and host defense mechanisms. In this study, we demonstrate that DNA from T. cruzi stimulates cytokine production by APCs in a TLR9-dependent manner and synergizes with parasite-derived GPI anchor, a TLR2 agonist, in the induction of cytokines by macrophages. Compared with wild-type animals, T. cruzi-infected Tlr9(-/-) mice displayed elevated parasitemia and decreased survival. Strikingly, infected Tlr2(-/-)Tlr9(-/-) mice developed a parasitemia equivalent to animals lacking MyD88, an essential signaling molecule for most TLR, but did not show the acute mortality displayed by MyD88(-/-) animals. The enhanced susceptibility of Tlr9(-/-) and Tlr2(-/-)Tlr9(-/-) mice was associated with decreased in vivo IL-12/IFN-gamma responses. Our results reveal that TLR2 and TLR9 cooperate in the control of parasite replication and that TLR9 has a primary role in the MyD88-dependent induction of IL-12/IFN-gamma synthesis during infection with T. cruzi.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / physiology*
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Adjuvants, Immunologic / physiology*
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Animals
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Chagas Disease / immunology*
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Chagas Disease / metabolism
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Chagas Disease / parasitology*
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Cytokines / biosynthesis
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Glycosylphosphatidylinositols / physiology
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Humans
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Inflammation Mediators / metabolism
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Interferon-gamma / metabolism
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Interleukin-12 / metabolism
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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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Signal Transduction / genetics
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Signal Transduction / physiology*
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Toll-Like Receptor 2 / deficiency
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / physiology*
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Toll-Like Receptor 9 / deficiency
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Toll-Like Receptor 9 / genetics
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Toll-Like Receptor 9 / physiology*
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Trypanosoma cruzi / genetics
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Trypanosoma cruzi / immunology*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Adjuvants, Immunologic
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Cytokines
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Glycosylphosphatidylinositols
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Inflammation Mediators
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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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Toll-Like Receptor 2
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Toll-Like Receptor 9
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Tumor Necrosis Factor-alpha
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Interleukin-12
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Interferon-gamma