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

Baum, Alina; García-Sastre, Adolfo

TLR3 was the first characterized receptor to induce IFN production in response to dsRNA. Mice lacking TLR3 were shown to be more resistant to poly(I:C) induced shock and TLR3 deficient macrophages exhibited reduced IFN Fig. 1 Endosomal and cytoplasmic pathways for virus recognition and IFN production. In DCs, TLR7 and TLR8 located in endosomal compartments recognize viral ssRNA through either direct infection, autophagocytic uptake of viral material from cytoplasm or phagocytic uptake of other infected cells or vial particles. Both TLR 7 and 8 signal through adaptor MyD88, which through interaction with IRAK4/IRAK1/TRAF6 complex leads to phosphorylation and activation of IRF7 and subsequent IFN transcription. TLR3 located in endosomes of cDCs, macrophages, epithelial cells, and fibroblasts is activated by encountering dsRNA. Following its activation, TLR3 signals through its adaptor, TRIF which leads to activation of noncanonical IKK kinases (TBK1/IKKe) and subsequent phosphorylation and nuclear translocation of IRF3. NF-jB is also activated by TRIF mediated signaling through canonical IKK kinases (IKKa, b, and c). Cytoplasmically located RIG-I and MDA5 are expressed in most cells and recognize 5 0 ppp containing dsRNA or long dsRNA, respectively. Both of these cytoplasmic sensors upon activation interact and signal through the mitochondrially located adaptor MAVS. This signaling pathway, analogous to that of TLR3, leads to activation of the canonical and noncanonical IKK kinases and the following nuclear transclocation of NF-jB and IRF3. Concurrent activation of IRF3 and NF-jB in turn allows for transcription of IFN genes and its synthesis and export production in response to poly(I:C) (Alexopoulou et al. 2001) . It was therefore proposed that this receptor was primarily responsible for detection of dsRNA generated during viral infections and induction of IFN. However, the physiological importance of TLR3 in IFN induction is questionable in light of a number of studies showing that loss of this receptor does not result in increased viral susceptibility or reduced IFN production in the infected animals. TLR3 knockout mice were shown to recover normally from multiple RNA viruses, including lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), and reovirus (ReV) (Edelmann et al. 2004; Johansson et al. 2007; Kato et al. 2005) . Infections of TLR3 knockout mice with mouse cytomegalovirus (MCMV), a dsDNA virus, has also led to contradictory outcomes with one group reporting normal recovery and IFN production and another reporting increased susceptibility and abrogated IFN levels (Edelmann et al. 2004; Tabeta et al. 2004 ). TLR3's role in cytokine production can be observed in TLR3 deficient human lung epithelial cells infected with influenza virus. In response to infection, these cells exhibit a reduced induction of NF-kB dependent genes but not of IRF3 dependent genes, including IFNb (Le Goffic et al. 2007 ). In addition to cytokine production, TLR3 signaling has also been implicated in cross-priming of CD8 T cells by DC mediated phagocytosis of infected cells (Schulz et al. 2005) , and in activation of NK cells in response to MCMV infection (Tabeta et al. 2004 ). Consistent with its role in inducing an inflammatory response, one study showed that mice lacking in TLR3 were more resistant to West Nile virus (WNV) associated encephalitis, presumably because of a break down in blood-brain barrier caused by TLR3 mediated