TLR-9 recognizes unmethylated CpG dinucleotides. In mammalian genomes, CpG dinucleotides in genomic DNA are heavily methylated on the cytosine by DNA mathyltransferases. But in the genomes of bacteria and many viruses,CpG dinucleotidees remain unmethylated and represent another pathogenassociated molecular pattern.
The delivery of TLR-3,TLR-7, and TLR-9 from the endoplasmic reticulum to the endosomes relies no their interaction with specific protein, UNC93B1, which is composed of 12 transmembrane domains. Mice lacking this protein have defects in signaling by these endosomal TLRs. Rare human mutations in UNC93B1 have been identified as causing susceptibility to herpes simplex encephalitis, similarly to TLR-3 deficiency, but do not impair immunity to many other viral pathogens, presumably because of the existence of other viral sensors, which are discussed later in this chapter.