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.

Transcriptional factor binding preference corresponds with differential ISG expression. For H1N1-09 infection, robust IFN expression syncs with observed global ISG induction (Fig. 1D ). In contrast, while the strong induction of type I and III IFN corresponds to previous reports for H5N1-VN1203 (14), the up-and downregulation of ISG subsets indicate that the global IFN response is altered by the more virulent influenza strain. Notably, while blocking recognition pathways and IFN signaling have been described as means to impair ISG induction (10, 17) , neither approach would directly result in ISG downregulation relative to mock. In fact, the results suggest that H5N1-VN1203 ISG antagonism occurs after pathway activation, possibly through interfering with transcriptional factor binding. However, ingenuity pathway analysis (IPA) of IRF7-, STAT1-, and NF-B-dependent genes demonstrated no uniform pattern of either specific induction or repression 12 h after H5N1-VN1203 infection (see Fig. S2A in the supplemental material; also, data not shown); in addition, IPA upstream Z scoring, a value based on downstream expression of connected genes, revealed lower activation scores for these transcriptional factors in H5N1-VN1203 than in H1N1-09 but no evidence of repression (Z score Ͻ Ϫ2.0), reflecting both increased and decreased downstream ISG expression (see Fig. S2B to D). The analysis suggested that H5N1-VN1203 does not achieve downregulation via blockade of transcriptional factors; instead, these data and IFN expression values indicate that upstream ISG signaling remains intact.