Bacterial DNA as an evolutionary conserved ligand signalling danger of infection to immune cells.

Abstract

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 cytokines. Cell-wall components of gram-positive and gram-negative bacteria, such as peptidoglycan, endotoxin or lipoteichoic acid, activate via CD14, a prototypic pattern-recognition receptor for carbohydrates. This review article focuses on an alternative recognition system of the innate 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-presenting cells. As a consequence bacterial DNA serves as an alternate ligand to signal danger of infection. Bacterial DNA and (synthetic) oligonucleotides (ODN) derived thereof are as efficient as endotoxin in activating macrophages and dendritic cells and in triggering release of pro-inflammatory cytokines. In mice sensitized with D-galactosamine (D-GalN), high doses of bacterial DNA from either gram-positive or gram-negative pathogens induce a lethal cytokine syndrome (lethal shock). Therefore, bacterial DNA may represent a hitherto unrecognized pathophysiological entity in host-parasite interactions. Moreover, recent evidence suggests that bacterial DNA or immunostimulating ODN triggers the immunostimulation of antigen-presenting cells, and can be utilized as adjuvant to enhance immune responses of the adaptive immune system towards poorly immunogenic antigens. In fact, foreign DNA might be useful as immunotherapeutically active adjuvant to direct adaptive immune responses towards Thl-dominated immune reactions. If these findings are operative in humans, immunostimulating ODN might be used to influence Th2-dominated diseases such as allergy.