Figure. Diagram showing how components of RNA viruses are recognized by TLRs located at the plasma membrane (TLR4, viral glycoprotein sensing) and in the endosomal compartment (TLR3, double-stranded RNA sensing; TLR7 and TLR8, both single-stranded RNA sensing). Virus replication intermediates and replicated genomes are also recognized by cytosolic RNA sensors, RIG-I, and MDA5. Downstream adaptor proteins, MyD88 for TLR4, TLR7, and TLR8; TRIF for TLR3 and TLR4, and MAVS (for MDA5 and RIG-I) are activated. These activations trigger signaling cascades through TRAF3 and TRAF6; TBK1; and IKKα, IKKβ, and IKKε, which leads to phosphorylation and nuclear translocation of NF-κB, IRF3, and IRF7. These changes result in production of proinflammatory cytokines and type I and type III IFNs. Secreted IFN-α/β and IFN-λ bind to their specific receptors (IFNAR and IFNLR) in infected and neighboring cells. Activation of JAK-1 and TYK-2 leads to phosphorylation of STAT1 and STAT2. After translocation in the nucleus, phosphorylated STAT1 and STAT2 form a complex with IRF9 to induce expression of ISGs, such as OAS-RNase L and PKR, and establishment of an antiviral program. IFN, interferon; IFNAR, IFN-α/β receptor; IFNLR, interferon-λ receptor; IKK, inhibitor of nuclear factor-κB kinase; ISGs, IFN-stimulated genes; IRF, IFN regulatory factor; JAK-1, Janus kinase 1; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated gene 5; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor-κB; OAS, 2′-5′ oligoadenylate synthetase; P, phosphorylated protein; PKR, protein kinase receptor; RNase L, latent endoribonuclease; RIG-I, retinoic acid‒inducible gene I; STAT, signal transducer and activator of transcription; TBK 1, TANK binding kinase 1; TLRs, Toll-like receptors; TRAF, tumor necrosis factor receptor-associated factor; TRIF, TIR-domain-containing adapter-inducing IFN-β; TYK-2, tyrosine kinase 2.