Selectivity of Human TLR9 for Double CpG Motifs and Implications for the Recognition of Genomic DNA

TLR9 acts as a first-line host defense against pathogens recognizing DNA comprising unmethylated CpG motifs present in bacteria and viruses. Species- and sequence-specific recognition differences were demonstrated for TLR9 receptors. Activation of human (h)TLR9 requires a pair of closely positioned...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2017-03, Vol.198 (5), p.2093-2104
Main Authors: Pohar, Jelka, Yamamoto, Chikako, Fukui, Ryutaro, Cajnko, Miša-Mojca, Miyake, Kensuke, Jerala, Roman, Benčina, Mojca
Format: Article
Language:English
Subjects:
Activation
Amino acid sequence
Animals
Bacteria
CpG islands
CpG Islands - genetics
Deoxyribonucleic acid
DNA
DNA, Bacterial - genetics
DNA, Bacterial - immunology
Genome - genetics
HEK293 Cells
Humans
Immunostimulation
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutagenesis
Mutation
Nucleotide Motifs - genetics
Nucleotide sequence
Oligodeoxyribonucleotides - genetics
Oligonucleotides
Pathogens
RAW 264.7 Cells
Receptor mechanisms
Selectivity
Signal Transduction
Species Specificity
TLR9 protein
Toll-Like Receptor 9 - genetics
Toll-Like Receptor 9 - metabolism
Toll-like receptors
Viruses
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Summary:TLR9 acts as a first-line host defense against pathogens recognizing DNA comprising unmethylated CpG motifs present in bacteria and viruses. Species- and sequence-specific recognition differences were demonstrated for TLR9 receptors. Activation of human (h)TLR9 requires a pair of closely positioned CpG motifs within oligodeoxyribonucleotides (ODNs), whereas mouse TLR9 is effectively activated by an ODN with a single CpG motif. Molecular model-directed mutagenesis identified two regions, site A and site B, as important for receptor activation. Amino acid residues Gln and Arg within site A contribute to the sequence-specific recognition by hTLR9 in determining the bias for two appropriately spaced CpG motifs within immunostimulatory ODNs. Mutation of Gln at site B, in combination with Gln and Arg mutations of mouse counterparts, increased activation of hTLR9 by mouse-specific ODN, mammalian genomic DNA, and bacterial DNA. We propose that the double CpG motif sequence-specificity of hTLR9 results in decreased activation by ODNs with a lower frequency of CpG motifs, such as from mammalian genomic DNA, which increases hTLR9 selectivity for pathogen versus host DNA.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1600757