Translating nucleic acid sensing pathways into therapies

Nucleic acid sensing initiates the immune defense against viruses and other pathogens. A hallmark consequence of nucleic acid receptor activation is the release of interferons (IFN), which promote protective immune responses via the expression of multiple interferon stimulated genes (ISG). A similar ISG signature is also found in autoinflammatory and autoimmune conditions, indicating that chronic activation of nucleic acid sensing pathways may contribute to these diseases. At both ends of this spectrum nucleic acid sensors and their signaling mediators emerge as highly attractive drug targets. Agonists are being developed as anti-infectives, immune stimulants or vaccine adjuvants, and antagonists as anti-inflammatory immune modulators. Here we review how nucleic acid sensing pathways are currently being targeted pharmacologically. We propose how the emerging wealth of molecular, mechanistic and clinical insight can be leveraged towards novel therapies of infections, cancer, autoimmune and autoinflammatory disorders, and how new agonists and antagonists of nucleic acid sensing pathways will in turn reinform our mechanistic understanding of these complex diseases