AVIAN INFLUENZA IMMUNE EVASION – SPECIES-SPECIFIC NS1 PROTEIN INTERACTIONS IN HUMAN AND DUCK HOSTS
Danyel Evseev, University of Alberta
Danyel Evseev1, Robert G. Webster2 and Katharine E. Magor1
1. Department of Biological Sciences and Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB
2. Division of Virology, Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN
The ability of influenza viruses to block innate immune responses during establishment is crucial to their success in a host. The influenza non-structural protein 1 (NS1) is the main viral antagonist to innate immunity within host cells. In humans NS1 blocks the RIG-I signaling pathway of viral detection, through interactions with several pathway components. We are investigating whether NS1 proteins interfere with duck RIG-I signaling, because ducks are the reservoir hosts of influenza and can mount robust innate immune responses to highly pathogenic flu strains that kill chickens and humans. We compared the ability of NS1 from several low pathogenic and highly pathogenic influenza strains to interact with an essential co-activator of RIG-I, the TRIM25 protein, and show that different NS1 proteins interact with the human versus the duck orthologues, despite similar subcellular distribution patterns. Notably, NS1 proteins from a fatal human influenza isolate and from a closely-related avian isolate have different binding affinities for human TRIM25. We also show that none of the NS1 proteins bind to the signalling domain of RIG-I directly, in either species. Work is ongoing to test interactions with other RIG-I pathway components, to determine by mutagenesis the critical amino acid residues in NS1 that determine these interactions, and to perform in vitro infections with recombinant viruses. Knowing the sequence features of NS1 that contribute to human virulence is important for global surveillance and disease control. Comparing this to the function of NS1 in ducks will expand our understanding of the changes that occur when influenza jumps the species barrier.
This study is supported by CIHR.