Abstract
Toll-like receptors (TLRs) are evolutionarily conserved proteins that recognize microbial molecules and initiate host defense. To investigate how TLRs work together to fight infections, we tested the role of TLRs in host defense against the Gram-negative bacterial pathogen, Salmonella. We show that TLR4 is critical for early cytokine production and killing of bacteria by murine macrophages. Interestingly, later on, TLR2, but not TLR4, is required for macrophage responses. Myeloid differentiation factor 88, an adaptor protein directly downstream of TLRs, is required for both early and late responses. TLR4, TLR2, and myeloid differentiation factor 88 are involved in murine host defense against Salmonella in vivo, which correlates with the defects in host defense observed in vitro. We propose a model where the sequential activation of TLRs tailors the immune response to different microbes.
MeSH terms
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Acute Disease
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Adaptor Proteins, Signal Transducing
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Administration, Oral
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Animals
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Antigens, Bacterial / administration & dosage
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Antigens, Bacterial / immunology
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Antigens, Differentiation / genetics
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Blood Bactericidal Activity / immunology
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Cytotoxicity, Immunologic / genetics
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Down-Regulation / immunology
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Genetic Predisposition to Disease
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Immunity, Innate / genetics
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Macrophages / immunology
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Macrophages / microbiology
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Membrane Glycoproteins / agonists
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred C3H
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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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Phenotype
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Receptors, Cell Surface / agonists
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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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Salmonella Infections, Animal / genetics
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Salmonella Infections, Animal / immunology*
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Salmonella Infections, Animal / microbiology
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Salmonella typhimurium / growth & development
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Salmonella typhimurium / immunology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Time Factors
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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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Up-Regulation / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Bacterial
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Antigens, Differentiation
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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, 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