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 differential ISG regulation at both the RNA and protein levels, we next sought to determine the means of control. One possible global mechanism is to prevent, disrupt, or delay initial induction of either type I or type III IFN, another important antiviral cytokine. While several IFN-independent ISGs exist, the vast majority of genes are augmented by IFN production (9); naturally, both CoV and influenza family members have developed approaches to prevent this induction by disturbing the sensing pathways (10, 11) . Yet, despite the presence of antagonists, both H5N1-VN1203 and H1N1-09 infection resulted in robust transcription of type I and type III IFN molecules ( Fig. 2A) ; IFN-␤1, IFN-␣5, and IFN-1 were each strongly induced in both influenza strains. These results are consistent with Table S1 in the supplemental material). All ISG and analysis available online as outlined in data dissemination (supplement). Viral titers (B) and viral genomic RNA (C) following infection of Calu3 cells previous reports for both viruses (13, 14) and indicated host recognition via intact sensing pathways despite the presence of IFN antagonists like NS1. In contrast, SARS-CoV infection resulted in IFN-␤ induction only after 12 h (Fig. 2) ; IFN-␣5 and IFN-1 were even further delayed and dampened compared to those in the influenza infections. Similarly, MERS-CoV failed to induce IFN genes prior to 12 h but also induced more robust IFN-␣5 relative to that of SARS-CoV, possibly implicating signaling differences in antagonism between the two CoVs. Together, the IFN induction data indicated that unlike the influenza strains, CoV infections more tightly block recognition and/or disrupt IFN induction. Coupled with previous reports of the sensitivity of SARS-and MERS-CoV to type I IFN (15, 16) , these data argued that delayed ISG expression enhances CoV infection.