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.

Following IFN-␣ treatment or infection, the ISG RNA expression patterns showed both similarities and stark contrasts (Fig. 1D ). H1N1-09 quickly and robustly induced the majority (97%) of ISGs, mimicking type I IFN treatment. However, H5N1-VN1203 induced robust induction in only 35% of the consensusannotated ISGs (log 2 FC of Ͼ0.75 at 24 h postinfection [hpi]) (Fig. 1D, orange panel) ; in contrast, a significant subset of ISGs (26%) had only minimal induction (green panel). Finally, the largest percentage (39%; log 2 FC of ϽϪ0.75 at 24 hpi, purple and blue panels) was downregulated relative to mock following H5N1-VN1203 infection. Based on these groupings, the same ISGs were almost uniformly upregulated in response to H1N1-09 infection (Fig. 1D ). In contrast, ISG expression was neither strongly up-nor downregulated following the first 12 h of SARS-CoV infection; only after 24 to 36 hpi are the majority (88% at 72 hpi) of ISGs induced. However, several ISGs showed only minimal, if any, stimulation (e.g., TLR3, SERPIN1), and ACE2, the receptor for SARS-CoV, was downregulated, corresponding with previous reports (12) . For MERS-CoV, the first 12 h also found no significant ISG induction, after which expression mirrored H5N1-VN1203 with upregulation (42%), no stimulation (39%), and downregulation (19%) of ISG subsets (see Table S1 ). Together, these results demonstrate contrasting and overlapping approaches used by H5N1-VN1203, H1N1-09, SARS-CoV, and MERS-CoV in their regulation of the global ISG response.