Sid, H.; von Heyl, T.; Schleibinger, S.; Klinger, R.; Guabiraba, R.; Guillory, V.; Schade, B.; Elleder, D.; Sives, S.; Vervelde, L.; Trapp, S.; Schusser, B.

Retinoic acid-inducible gene I (RIG-I) activates mitochondrial antiviral signaling proteins, initiating the antiviral response. RIG-I and RNF135, a ubiquitin ligase regulator, are missing in domestic chickens but conserved in mallard ducks. It was long believed that chickens\' RIG-I loss was linked to increased avian influenza susceptibility. We restored both genes in chickens and examined their susceptibility to the avian influenza virus H7N1. Uninfected RIG-I-expressing chickens exhibited shifts in T and B cells, while the H7N1 infection led to severe disease, persistent weight loss, and increased viral replication. Conversely, the co-expression of RIG-I and RNF135 reduced the viral replication and was associated with high inflammatory response. Our data indicate that the loss of RIG-I in chickens likely evolved to counteract deleterious inflammation caused by viral infection. We highlight the effects of restoring evolutionary lost genes in birds and suggest a new immunological approach to reduce viral replication and prevent infection.