The study investigates the antiviral responses mediated by RIG-I, an RNA helicase enzyme, to single-stranded (ss) viral genomic RNA bearing 5' phosphates. The research reveals that influenza A virus infection does not generate double-stranded RNA (dsRNA), which is typically believed to trigger antiviral immunity. Instead, RIG-I is activated by ssRNA with 5' phosphates, a process blocked by the influenza protein NS1. This suggests that RIG-I can sense uncapped ssRNA and that its ability to do so may have evolved as a means of distinguishing viral from self RNA. The study also shows that RIG-I forms stable complexes with RNA containing 5' phosphates, and that NS1 recruits RIG-I to these complexes. These findings highlight the role of RIG-I in recognizing viral ssRNA and provide insights into how some viruses can be efficiently recognized by the immune system despite producing little or no dsRNA.The study investigates the antiviral responses mediated by RIG-I, an RNA helicase enzyme, to single-stranded (ss) viral genomic RNA bearing 5' phosphates. The research reveals that influenza A virus infection does not generate double-stranded RNA (dsRNA), which is typically believed to trigger antiviral immunity. Instead, RIG-I is activated by ssRNA with 5' phosphates, a process blocked by the influenza protein NS1. This suggests that RIG-I can sense uncapped ssRNA and that its ability to do so may have evolved as a means of distinguishing viral from self RNA. The study also shows that RIG-I forms stable complexes with RNA containing 5' phosphates, and that NS1 recruits RIG-I to these complexes. These findings highlight the role of RIG-I in recognizing viral ssRNA and provide insights into how some viruses can be efficiently recognized by the immune system despite producing little or no dsRNA.