BACTERIAL-DNA AS AN EVOLUTIONARY CONSERVED LIGAND SIGNALING DANGER OFINFECTION TO IMMUNE CELLS

During infection, the innate limb of the immune system senses danger ( pathogens) via constitutively expressed pattern-recognition receptors, and responds with activation and secretion of pro-inflammatory cytoki nes. Cell-wall components of gram-positive and gram-negative bacteria, such as peptidoglycan, endotoxin or lipoteichoic acid, activate via C D14, a prototypic pattern-recognition receptor for carbohydrates. This review article focuses on an alternative recognition system of the in nate immune system for the recognition of bacterial DNA. Bacterial DNA differs from eukaryotic DNA in its frequency of the dinucleotides CG and its lack of methylation. These structural differences appear to be sensed by cells of the innate immune system such as antigen-presentin g cells. As a consequence bacterial DNA serves as an alternate ligand to signal danger of infection. Bacterial DNA and (synthetic) oligonucl eotides (ODN) derived thereof are as efficient as endotoxin in activat ing macrophages and dendritic cells and ill triggering release of pro- inflammatory cytokines. In mice sensitized with D-galactosamine (D-Gal N), high doses of bacterial DNA from either gram-positive or gram-nega tive pathogens induce a lethal cytokine syndrome (lethal shock). There fore, bacterial DNA may represent a hitherto unrecognized pathophysiol ogical entity in host-parasite interactions. Moreover, recent evidence suggests that bacterial DNA or immunostimulating ODN triggers the imm unostimulation of antigen-presenting cells, and can be utilized as adj uvant to enhance immune responses of the adaptive immune system toward s poorly immunogenic antigens, In fact, foreign DNA might be useful as immunotherapeutically active adjuvant to direct adaptive immune respo nses towards Th1-dominated immune reactions. If these findings are ope rative in humans, immunostimulating ODN might be used to influence Th2 -dominated diseases such as allergy.