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.

Having established NS1 as a required component for strong ISG manipulation and downregulation, we next sought to determine if histone modifications of specific ISGs were modified in H5N1-NS1trunc124 infections. For this, we repeated the ChIP-PCR experiment with WT and NS1trunc124 viruses ( Fig. 5B and C). Similar to what was previously observed, ISGs that were transcriptionally downregulated in WT infections (i.e., SMAD9L, CFHR1, and DDX58) were strongly associated with repressed histones (H3K27me3) and only weakly associated with active histones (H3K4me3). In contrast, the absence of full-length NS1 resulted in augmented association of the same transcripts with the active H3K4me3 and reduced binding to the inhibitory H3K27me3 mark. Together, the data demonstrated that histone modifications were altered in the absence of full-length NS1 and may result in the augmented ISG RNA and protein expression following NS1trunc124 mutant virus infection.