Standing on three legs: antiviral activities of RIG-I against influenza viruses

Influenza A virus (FLUAV) is a severe pathogen of humans, able to unleash epidemics and pandemics of respiratory disease. For the host to survive virus infection, it is essential to rapidly recognize the pathogen and induce the synthesis of antiviral type I interferons (IFNs). The IFN system provides a broad spectrum of sensors that respond to conserved, virus-associated molecular patterns. For FLUAV, the RNA helicase RIG-I represents the major innate immune sensor, mainly binding and reacting to the 5' triphosphate dsRNA 'panhandle' that is formed by the conserved 5' and 3' end sequences of the viral ssRNA genome. Besides the well-known function of RIG-I in the signaling chain that leads to IFN induction, recent data suggests that RIG-I performs also other antiviral activities. In this review, we summarize the current knowledge on RIG-I-mediated recognition of FLUAV, and how RIG-I interferes with virus replication. We will highlight three major functions of RIG-I against FLUAV: IFN induction, signaling-independent direct antiviral activity, and assembly of an inflammasome.