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.

We next sought to determine if NS1 from another highly pathogenic virus mediated a similar global ISG response. With this in mind, a meta-analysis was conducted on mRNA expression data from A549 cells infected with pandemic 1918 H1N1 and a 1918 H1N1 mutant expressing NS1 from a seasonal H1N1 strain (A/Texas/36/91 [TX]) (33) . Each of these viruses maintained a full-length NS1 but lacked the histone mimic motif found in H3N2. Confirming the original findings, several ISGs had a substantial increase in expression after infection with recombinant virus encoding the TX NS1 compared to the WT 1918 NS1 (Fig. 5D) . However, expanding the examination to the consensus ISG list derived from Calu3 cells to the A549 cell metadata revealed that expression of ISGs was not uniformly downregulated with 1918 NS1. Instead, many ISGs had equivalent expression levels, and several (IFITM1, ZBP1, HSH2D, etc.) had greater expression with 1918 NS1 than TX NS1. These results suggest that NS1 substitution from a more virulent strain does not always result in uniform ISG augmentation but rather targets ISG manipulation based on strain specific NS1 activity. Notably, ISG downregulation was absent in the less virulent TX NS1 (0 genes) compared to in the 1918 NS1 (21% ϽϪ0.25 log 2 FC at 24 hpi); coupled with data from H5N1-VN1203 and MERS-CoV infections, these results suggest that pathogenic respiratory viruses may downregulate a subset of ISGs via histone modification and contribute to effective infection and enhanced virulence.