CpG DNA Induces Sustained IL-12 Expression In Vivo and Resistance to Listeria monocytogenes Challenge

Vertebrates have evolved innate immune defense mechanisms that recognize and respond to structural patterns that are specific to microbial molecules. One such pattern recognition system is based on unmethylated CpG dinucleotides in particular sequence contexts (CpG motifs); these motifs are common in bacterial DNA but are under-represented ("CpG suppression") and methylated in vertebrate DNA. Mice that are injected with bacterial DNA or synthetic oligodeoxynucleotides (ODNs) containing CpG motifs respond with a rapid production of IL-12 and IFN-gamma. The serum levels of IL-12 were increased for at least 8 days after a single injection of CpG ODNs, but IFN-gamma levels returned to baseline within 24 h. This Th1-like cytokine response to CpG motifs induces a state of resistance to infection by Listeria monocytogenes in susceptible specific pathogen-free BALB/c mice. Resistance developed within 48 h of pretreatment with CpG ODNs, persisted for at least 2 wk, and was dependent upon IFN-gamma secretion. These data support the hypothesis that CpG DNA motifs are a "danger signal" that activates protective innate immune defenses and may have therapeutic potential.