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

Baum, Alina; García-Sastre, Adolfo

An interesting possibility for RIG-I activation could involve production of cellular RNAs capable of acting as substrates following the initial detection of viral infection. This type of mechanism would act to stimulate IFN production under conditions where viral substrates were limiting, as would presumably be the case early in infection. Indeed, one example of such a mechanism appears to be the production of stimulatory RNAs by RNAse L digestion of cellular mRNA. The resultant small RNAs, with possible double-stranded composition and 3 0 monophosphates, induced an IFN-b reporter in a RIG-I and MDA5 dependent manner (Malathi et al. 2007) . Another example of cell-mediated synthesis of a RIG-I substrates comes from two recent studies examining the previously reported (Cheng et al. 2007; Rasmussen et al. 2007 Rasmussen et al. , 2009 Samanta et al. 2006 ) involvement of the RIG-I pathway in response to DNA viruses and intracellular bacteria (Ablasser et al. 2009; Chiu et al. 2009 ). Both reports demonstrate that poly(dA:dT) when introduced into cells served as a template for DNA Polymerase III synthesis of 5 0 ppp containing dsRNA molecules which in turn activated RIG-I signaling. Inhibition of Pol III activity in infected cells led to loss of IFN induction following infection with DNA viruses, such as Epstein-Barr virus, herpes simplex virus 1 and adenovirus, and intracellular bacterium Legionella pneumophila. Thus, in addition to being the primary receptor for RNA viruses, RIG-I might potentially play an important role in recognition of some DNA viruses and intracellular bacteria.