ABSTRACT
In the search for inducers of anti-viral interferons (IFNs), several groups in the early 1960s found that viral and other nucleic acids (RNA as well as DNA) can trigger the production of interferons that protect host cells from the cytopathic effects of viruses.1-3 Isaacs et al. noted that influenza virus particles containing nucleic acids were able to induce virus interference; virus particles lacking nucleic acids cannot do so.3 In a series of papers by Hilleman’s group published in 1967 in PNAS, it was shown that double-stranded (ds) RNA isolated from reovirus, virus-infected bacteria, and fungi, as well as dsRNA in the form of synthetic polynucleotides, were highly active IFN inducers.4-7
Field et al. demonstrated that poly I:C was one of the most potent polynucleotides to induce type I interferon responses in rabbits and mice.5 Several decades after these observations were made, the molecular pathways that mediate immune responses to dsRNA were recognized. Toll-like receptor (TLR) 3 was identified as a receptor for dsRNA,8 which we now know is mainly active intracellularly in specific dendritic cell (DC) subpopulations.9 Two cytosolic receptors, the caspase recruitment domain (CARD) containing RNA-helicases RIG-I (retinoic acid-inducible gene I) and Mda5 (melanoma differentiation antigen 5), that sense RNAs of replicating viruses in all cell types, have been found only recently.10-12
In addition to these cytoplasmatic dsRNA recognition mechanisms, TLR7 and TLR8, which are localized in endosomal compartments, have been identified as receptors for GU-rich ssRNA derived from viruses (such as influenza) and autoimmune complexes containing self RNA.13-16 The significance of these findings for anti-viral immune defense and autoimmunity will be discussed in detail below.
