Influenza virus antagonizes self-sensing by RIG-I to enhance viral replication

Innate immune sensors must finely distinguish pathogens from the host to mount a response only during infection. RIG-I is a cytoplasmic sensor that triggers a broad antiviral response in response to sensing foreign RNAs. Here, we show that RIG-I not only binds viral RNAs but is activated by host RNAs. These are primarily non-coding RNAs transcribed by RNA polymerase III. They are benign under normal conditions but become immunogenic during influenza virus infection, where they signal via RIG-I to suppress viral replication. These RNAs are also bound by influenza virus nucleoprotein (NP), which normally functions to encapsidate the viral genome. NP interacts with RIG-I via an RNA bridge and antagonizes sensing of self-RNAs to counter innate immune responses. Overall, we demonstrate that self-sensing is strategically deployed by the cell to amplify the antiviral response and reveal a newly identified viral countermeasure that disrupts RIG-I activation by host RNAs.