TLR-dependent and independent IFN-I induction, signaling and action. PAMP recognition by PRRs including TLR3 and RIG-I/MDA-5 leads to activation of transcription factors involved in activation of the IFNβ promoter (P). IRF3 is able to activate initial transcription of ISRE promoters by itself (red arrow). Following synthesis, IFNβ is secreted and binds to its receptor to activate the expression of ISGs via the JAK/STAT pathway. ISGs encode proteins with antiviral activity to control viral infection and other factors including IRF7, which leads to production of IFNα, amplifying the IFN-I response. In pDCs, ligation of TLR 7/8 or 9 can also lead to up-regulation of IFN-I production via IRF-7 (which is constitutively expressed in these cells). Different viral mechanisms counteract the IFN-I response at different steps: (1) access of viral PAMPs to PRRs involved in INF-I induction, (2) IFN-I induction, (3) IFN-I signaling, (4) activity of antiviral products, and (5) IFN-I-receptor binding. For more details, see text.