Grant: Project Grant

Influenza A virus (IAV) is an important human respiratory pathogen that causes annual epidemics and occasionally pandemics, posing severe public concerns. Innate immunity is the first line of the host defense system that detects and defenses against virus infection. IAV infection is detected largely by an intracellular sensor, a protein called retinoic acid inducible gene-I (RIG-I). RIG-I has long been thought to be exclusively cytoplasmic. Interestingly, IAV represents few of the RNA viruses that replicate in the nucleus. How does a cytoplasmic sensor recognize a nuclear replicating virus has been puzzling the field. We recently showed that RIG-I, in addition to being in the cytoplasm, also resides in the nucleus and is critical to mount innate response to IAV infection. The current project will characterize RIG-I interactions with IAV. We propose three aims: to characterize the signaling cascades arising from nuclear RIG-I; to characterize how the aberrant viral RNA generated during IAV infection are recognized by cytoplasmic and nuclear RIG-I; and to examine the role of nuclear RIG-I functions in response to IAV infection in mice. The knowledge gained from this project will provide a new rationale that paves the way for a better control of influenza infection and disease.