Activation of TLR3 by viral dsRNA leads to the recruitment of Toll/IL-1R homology domain–containing adaptor-inducing IFN-γ (TRIF), which activates TNF receptor–associated factor 6 (TRAF6), TANK-binding kinase 1/IκB kinase i (TBK1/IKKi), and receptor-interacting protein 1 (RIP1). TBK1 phosphorylates the IFN regulatory factors (IRFs) 3 and 7. Cytoplasmic dsRNA is also recognized by the RLH system, which interacts with MAVS via caspase recruitment domains (CARDs). MAVS recruits IKK and TBK1, and this converges with TLR3 signaling and leads to NF-κB activation and the induction of type I IFNs (e.g., INF-α and INF-β). MAVS also activates NF-κB through Fas-associated death domain–containing protein (FADD) and RIP1 interaction. The binding of type I IFNs to their receptor (IFNR) causes JAK/STAT-mediated synthesis of IFN-stimulated gene (ISG) products, including PKR. Although it is unclear whether PKR may be directly stimulated by the interaction of MAVS and dsRNA (as indicated by the dashed arrow), the endogenous protein PACT/RAX can also activate PKR independently of dsRNA. As suggested by the results of the current study by Kang et al. (5), cigarette smoke may (as reflected by dashed arrows) affect lung cell responses to RNA viruses by enhancing MAVS-PKR signaling and therefore trigger alveolar cell death. Figure modified with permission from Nature Immunology (9) and Cell Research (12).