Pathogenic Influenza Viruses and Coronaviruses Utilize Similar and Contrasting Approaches To Control Interferon-Stimulated Gene Responses

Menachery, Vineet D.; Eisfeld, Amie J.; Schäfer, Alexandra; Josset, Laurence; Sims, Amy C.; Proll, Sean; Fan, Shufang; Li, Chengjun; Neumann, Gabriele; Tilton, Susan C.; Chang, Jean; Gralinski, Lisa E.; Long, Casey; Green, Richard; Williams, Christopher M.; Weiss, Jeffrey; Matzke, Melissa M.; Webb-Robertson, Bobbie-Jo; Schepmoes, Athena A.; Shukla, Anil K.; Metz, Thomas O.; Smith, Richard D.; Waters, Katrina M.; Katze, Michael G.; Kawaoka, Yoshihiro; Baric, Ralph S.

Mechanistically, C-terminal truncation of NS1 ablated global ISG antagonism for H5N1-VN1203. While mutations in PB1-F2 and PB2 resulted in significant ISG augmentation, the majority of ISGs maintain low or downregulated expression. In contrast, NS1 truncation halted ISG downregulation by H5N1-VN1203 and enhanced expression of a significant subset of ISGs at both the RNA and protein levels. This ISG stimulation occurred despite the presence of both the RNA-binding domain and part of the effector domain for NS1 (45) . Infection with the NS1 truncation mutant also resulted in reduced association with the repressive H3K27me3 and increased association with the active H3K4me3, identifying a role for NS1 in altered histone modification. Together, the data indicate a role for NS1 beyond just IFN pathway inhibition and identifies histone modification as a new target for ISG antagonism in H5N1-VN1203 infection.