Innate Immune Sensing of DNA

When a pathogen attacks, the immune system rapidly mobilizes host defenses in order to reduce the microbial burden and limit damage to the host [1]. Innate immunity is the first line of defense and relies on germ line–encoded pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs), which sense microbial products that are not normally found on or in mammalian cells. The considerable potency of nucleic acids as triggers of the innate immune response has gained appreciation over the last few years. In particular, nucleic acid sensing of viruses is central to anti-viral defenses through recognition of viral genomes or nucleic acids generated during viral replication. Distinct classes of nucleic acid sensing molecules have been uncovered that function in different cell types and subcellular compartments to coordinate innate defenses (reviewed in [2]). While recognition of RNA molecules is dependent on members of the TLR family and cytosolic RNA helicases, the mechanisms underlying the sensing of DNA have been less well defined. It has been known for over a decade that DNA, the most recognizable unit of life, is a potent trigger of inflammatory responses in cells. The discovery of TLR-9, a receptor for hypomethylated CpG-rich DNA, partially explained these findings [3]. TLR9 is localized to the endosomal compartment and in humans is expressed in B cells as well as in plasmacytoid dendritic cells (pDCs). However, it became clear that the immune stimulatory activity of microbial DNA was not compromised in many cells lacking TLR9 [4]. These observations prompted new efforts to understand how DNA triggers immune responses, an endeavor that has led to the discovery of several new DNA recognition receptors and fresh insights into infectious as well as autoimmune diseases.