I n the last few years we have witnessed an enormous improvement in our understanding of the delineation of TLR signaling, particularly in relation to the pathways that regulate IRF activation. The TLR pathway is particularly important in the pDCs for the detection of viral RNA and DNA associated with endocytosed viral particles. However, it is now becoming increasingly clearer that, in most other cell types, TLR-independent sensors are more critical for antiviral defenses. These TLR-independent sensors include the recently discovered cytoplasmic RNA helicases, RIG-I (Yoneyama et al. 2004) and Mda-5 (Kang et al. 2004) and a putative cytosolic DNA sensor, which remains to be defined. Signaling through these cytoplasmic receptors converges on many of the same signaling intermediates as those employed by the TLRs. Elucidation of the cross-talk between these different sensors and pathways in the response to a given virus remains a key challenge in our quest to understand innate immunity to viruses.
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