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

Baum, Alina; García-Sastre, Adolfo

Unlike TLR3, which is expressed in numerous cell types, TLR7 and 8 are mainly found in endosomal compartments of plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs), respectively (Diebold 2008) . The two receptors are very closely related and are thought to differ primarily in cell-type specificity and cytokine expression profiles (Gorden et al. 2005 ). Both TLR 7 and 8 have been determined to be activated by ssRNA rich in guanosine or uridine, and ssRNA from viruses, such as human immunodeficiency virus (HIV), VSV, and influenza A virus (Diebold et al. 2004; Heil et al. 2004; Lund et al. 2004 ). Interestingly, TLR7 was also shown to be activated by cellular mRNA but not by rRNA or tRNA, highlighting the possible importance of cellular RNA modifications in preventing stimulation of antiviral RNA receptors (Kariko et al. 2005 ). Based on their endoplasmic location and inaccessibility to cytoplasmically replicating viruses, TLRs can only be activated by viruses through endocytosis, or by phagocytic/autophagocytic uptake of viral RNA from the cytoplasm of infected cells. Therefore, viruses which enter cells through the endosomes, such as influenza virus, might be more easily detected by TLRs than viruses that do not use the endosome for entry (Diebold et al. 2004 ). On the other hand, autophagy has been shown to be necessary in pDC virus detection of VSV and Sendai virus, which enter cells through direct fusion with the plasma membrane. Accordingly, mice deficient in autophagy related gene 5 (Atg5) or pDCs treated with autophagy inhibitors produced much lower amount of IFN than wild type mice and only responded to replication competent viruses (Lee et al. 2007 ). An important role for TLR7 signaling came from studies that showed that both TLR7 (and its adaptor MyD88) are essential for IFN production by pDCs following influenza A virus and VSV infections . The unique dependence of pDCs on TLR7 signaling is intriguing in light of these cells' characterized ability to produce copious amounts of type I IFN in vitro and their role in IFN production in vivo (Asselin-Paturel et al. 2001) . Contrary to pDCs, other cell types have been shown to primarily rely on RLR sensors for RNA virus detection . A study by Kumagai et al. provides a nice illustration of a possible physiological reason for two parallel IFN inducing systems. In this study, mice were intranasally infected with either wild type or C protein deficient Sendai virus (SeV). The authors went onto show that pDCs, in a MyD88-dependent manner, were the primary IFN producing cells in response to wild type SeV. However, when SeV lacking in C protein were used, the primary IFN producers were alveolar macrophages. These cells did not rely on MyD88-directed signaling for IFN production, but instead depended on MAVS (an adaptor for RIG-I/MDA5 pathway) (Kumagai et al. 2007) . Since SeV C protein is known to inhibit RIG-I mediated IFN induction it appears that TLR-dependent pDCs are employed as primary IFN producing cells in the event that MAVS signaling is abrogated by the virus (Strahle et al. 2007 ). Thus, Induction of type I interferon by RNA viruses 1287 TLR-mediated recognition of viruses might be important for those pathogens, which have evolved mechanisms that subvert cytoplasmic viral sensors. TLR7 signaling has also been implicated in having a role in mediating the antibody response to RNA viruses, as MyD88 knockout mice are deficient in B cell IgG class-switching follo