Toll-like receptors involved in the response to microbial pathogens: development of agonists for toll-like receptor 9

Upon microbial infection, a host has to mount a multiplicity of immune responses that target the invading pathogen. This is achieved in part by the use of particular receptors expressed on mammalian innate immune cells, the toll-like receptors (TLRs). Recognition of a given microbial molecular structure, such as bacterial or viral DNA, leads to the activation of signaling pathways that result in distinct sets of immune responses. The pathogen structures that are recognized by TLR9 in bacterial or viral DNA are deoxycytidyl-deoxyguanosine dinucleotides (CpGs) in specific sequence contexts (CpG motifs). The stimulatory activity of pathogen DNA can be mimicked by synthetic oligodeoxynucleotides (ODNs) containing such motifs (CpG ODNs). The TLR9-mediated stimulation of the vertebrate innate immune system, and subsequently of the adaptive immune system, allows the use of TLR9 agonists as highly effective vaccine adjuvants for infectious diseases, and as stand-alone therapies or in combination with other therapies in cancer.