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

Koichi Tabeta, Philippe Georgel, Edith Janssen, Xin Du, Kasper Hoebe, Karine Crozat, Suzanne Mudd, Louis Shamel, Sosathya Sovath, Jason Goode, Lena Alexopoulou, Richard A. Flavell, Bruce Beutler

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755 Scopus citations

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 (Tlr9CpG1). Mice homozygous for the Tlr9CpG1 allele are highly susceptible to mouse cytomegalovirus infection and show impaired infection-induced secretion of IFN-α/β 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 IIFN production, neither pathway offers full protection against mouse cytomegalovirus infection in the absence of the other. The Tlr9CpG1 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 Tlr9CpG1 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.

Original languageEnglish (US)
Pages (from-to)3516-3521
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number10
DOIs
StatePublished - Mar 9 2004

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    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, B. (2004). Toll-like receptors 9 and 3 as essential complonents of innate immune defense against mouse cytomegalovirus infection. Proceedings of the National Academy of Sciences of the United States of America, 101(10), 3516-3521. https://doi.org/10.1073/pnas.0400525101