Defective RNA sensing by RIG-I in severe influenza virus infection

Summary

Influenza virus infection causes worldwide seasonal epidemics. Although influenza usually is a mild disease, a minority of patients experience very severe fulminating disease courses. Previous studies have demonstrated a role for type I interferon (IFN) in antiviral responses during influenza. However, IFN regulatory factor (IRF)7 deficiency is so far the only genetic cause of severe influenza described in humans. In this study we present a patient with severe influenza A virus (IAV) H1N1 infection during the 2009 Swine Flu pandemic. By whole exome sequencing we identified two variants, p.R71H and p.P885S, located in the CARD and RNA binding domains, respectively, of DDX58 encoding the RNA sensor RIG-I. These variants significantly impair the signaling activity of RIG-I. Similarly, patient cells demonstrate decreased antiviral responses to RIG-I ligands as well as increased pro-inflammatory responses to IAV, suggesting dysregulation of the innate immune response with increased immunopathology. We suggest that these RIG-I variants may have contributed to severe influenza in this patient and advocate that RIG-I variants should be sought for in future studies of genetic factors influencing single-stranded RNA virus infections. This article is protected by copyright. All rights reserved.