PMID:14993594

Citation	Tabeta, K, Georgel, P, Janssen, E, Du, X, Hoebe, K, Crozat, K, Mudd, S, Shamel, L, Sovath, S, Goode, J, Alexopoulou, L, Flavell, RA and Beutler, B (2004) Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc. Natl. Acad. Sci. U.S.A. 101:3516-21
Abstract	Several subsets of dendritic cells have been shown to produce type I IFN in response to viral infections, thereby assisting the natural killer cell-dependent response that eliminates the pathogen. Type I IFN production can be induced both by unmethylated CpG-oligodeoxynucleotide and by double-stranded RNA. Here, we describe a codominant CpG-ODN unresponsive phenotype that results from an N-ethyl-N-nitrosourea-induced missense mutation in the Tlr9 gene (Tlr9(CpG1)). Mice homozygous for the Tlr9(CpG1) allele are highly susceptible to mouse cytomegalovirus infection and show impaired infection-induced secretion of IFN-alpha/beta and natural killer cell activation. We also demonstrate that both the Toll-like receptor (TLR) 9 --> MyD88 and TLR3 --> Trif signaling pathways are activated in vivo on viral inoculation, and that each pathway contributes to innate defense against systemic viral infection. Whereas both pathways lead to type I IFN production, neither pathway offers full protection against mouse cytomegalovirus infection in the absence of the other. The Tlr9(CpG1) mutation alters a leucine-rich repeat motif and lies within a receptor domain that is conserved within the evolutionary cluster encompassing TLRs 7, 8, and 9. In other TLRs, including three mouse-specific TLRs described in this paper, the affected region is not represented. The phenotypic effect of the Tlr9(CpG1) allele thus points to a critical role for TLR9 in viral sensing and identifies a vulnerable amino acid within the ectodomain of three TLR proteins, essential for a ligand response.
Links	PubMed PMC373494 Online version:10.1073/pnas.0400525101
Keywords	Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Antigens, Differentiation/genetics; Antigens, Differentiation/metabolism; Cytokines/biosynthesis; Cytomegalovirus Infections/genetics; Cytomegalovirus Infections/immunology; DNA, Complementary/genetics; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Immunity, Innate/drug effects; Immunity, Innate/genetics; Killer Cells, Natural/immunology; Membrane Glycoproteins/deficiency; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Molecular Sequence Data; Mutation, Missense; Myeloid Differentiation Factor 88; Oligodeoxyribonucleotides/genetics; Oligodeoxyribonucleotides/pharmacology; Phenotype; Point Mutation; Receptors, Cell Surface/deficiency; Receptors, Cell Surface/genetics; Receptors, Cell Surface/metabolism; Receptors, Immunologic/deficiency; Receptors, Immunologic/genetics; Receptors, Immunologic/metabolism; Sequence Homology, Amino Acid; Signal Transduction; Toll-Like Receptor 3; Toll-Like Receptor 9; Toll-Like Receptors
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