Induction of type I interferon by RNA viruses: cellular receptors and their substrates

Baum, Alina; García-Sastre, Adolfo

Shortly following the discovery of IFN, viral RNA was proposed to be the inducer of this antiviral response (Isaacs et al. 1963) . Many early studies focused on possible nucleic acid inducers and numerous synthetic and biological RNAs were tested for their ability to induce interferon. Common to most of these studies, dsRNA was found to be a potent trigger of the interferon response unlike ssRNA, DNA or RNA:DNA hybrids (Colby and Morgan 1971) . Specifically, dsRNA from bacteria, reovirus, vaccinia virus and synthetic polyinosinic:polycytidylic acid poly(I:C) were shown to be potent activators of the antiviral response (Colby and Duesberg 1969; Field et al. 1967 Field et al. , 1968 Lampson et al. 1967; Tytell et al. 1967 ). Since then many groups have confirmed the strong IFN inducing ability of poly(I:C). The biochemical basis for its high level of activation remains unclear to this day, as it does not appear that stability of the RNA complex directly correlates with its IFN inducing capacity (Colby and Morgan 1971) . Based on dsRNA's induction capacity, the concept of dsRNA as a physiological viral trigger for IFN induction quickly became accepted in the field despite prevailing evidence that the majority of RNA viruses employ mechanisms that protect their RNA from exposure. This conundrum was largely dismissed with the simple explanation that viruses are bound to make mistakes during replication and are therefore likely to expose at least some dsRNA molecules to the cell. However, studies employing dsRNA-specific antibodies have shown that negative-strand RNA viruses do not appear to produce detectible amounts of dsRNA ). Although, it is possible that the threshold amount of dsRNA required to trigger an IFN response is below the antibody detection limit or that the length of dsRNA molecules is not sufficient for antibody recognition. But it is equally plausible that a different molecule serves as the primary recognition motif for RNA viruses.