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.

For influenza viruses, ISG expression differences between H5N1-VN1203 and H1N1-09 highlighted possible virulence determinants. Numerous reports have shown that specific influenza proteins impede the type I IFN response by targeting host signaling molecules and transcription factors (9, 10); together, the studies imply that disruption of these components results in a loss or dampening of the entire pathway's downstream components. However, robust IFN production following H5N1-VN1203 infection confounds this interpretation (21) (22) (23) ; instead, these data argue that during H5N1-VN1203 infection, host recognition and IFN signaling remain largely intact and a hierarchy in ISG activation exists. In contrast, the less virulent H1N1-09 virus lacks similar ISG antagonism both at the RNA and protein levels. Several HPAI viral protein functions may have contributed to ISG downregulation prior to mRNA production, including cap snatching, cleavage and polyadenylation specificity factor (CPSF) interference, and/or microRNA targeting (42) (43) (44) . However, each possibility would lead to nonspecific degradation of mRNA and thus could not explain the differential ISG expression observed in these studies. In contrast, significant changes in histone activation and repression marks, coupled with interaction with histone components (21) (22) (23) and the recent discovery of a histone mimic in H3N2 infection (17, 24) , provided a rational avenue for the observed contrast in ISG antagonism.