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Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection

Academic Article
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Overview

authors

  • Tabeta, K.
  • Georgel, P.
  • Janssen, E.
  • Du, X.
  • Hoebe, K.
  • Crozat, K.
  • Mudd, S.
  • Shamel, L.
  • Sovath, S.
  • Goode, J.
  • Alexopoulou, L.
  • Flavell, R. A.
  • Beutler, Bruce

publication date

  • March 2004

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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.

subject areas

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Antigens, Differentiation
  • Cytokines
  • Cytomegalovirus Infections
  • DNA, Complementary
  • DNA-Binding Proteins
  • Immunity, Innate
  • Killer Cells, Natural
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Mutation, Missense
  • Myeloid Differentiation Factor 88
  • Oligodeoxyribonucleotides
  • Phenotype
  • Point Mutation
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Toll-Like Receptor 3
  • Toll-Like Receptor 9
  • Toll-Like Receptors
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Identity

PubMed Central ID

  • PMC373494

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0400525101

PubMed ID

  • 14993594
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Additional Document Info

start page

  • 3516

end page

  • 3521

volume

  • 101

issue

  • 10

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