IFIH1 and infection: While it is possible that the genomes from incoming viruses are detected by sensors such as MDA5 in the cytosol, this is unlikely as proteinase K treatment prior to transfection of viral RNA or gamma irradiation pre-infection abrogates IFN induction [46], suggesting that viral replication is required for the generation of the norovirus PAMPs detected by the PRRs (Fig. 2).