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 demonstrated significant differences in histone modification patterns that correlate with expression outcomes between influenza strains, we returned to the CoVs. While both MERS-CoV and SARS-CoV maintain delayed IFN induction (Fig. 2) , MERS-CoV also downregulated a subset of ISGs with kinetics similar to those of H5N1-VN1203 (Fig. 1D) ; no similar subset was observed during SARS-CoV infection. Given its increased sensitivity to type I IFN (15, 16) , one possibility is that MERS-CoV employed an additional layer of ISG antagonism via altered histone modification. To test this idea, ChIP-PCR was again employed following both MERS-CoV and SARS-CoV infection. The results demonstrated that two genes (TLR3 and CFHR1) downregulated in both H5N1-VN1203 and MERS-CoV, but not SARS-CoV infection, had decreased association with activating H3K4me3 (Fig. 4C ) and increased association with the repressive H3K27me3 motif (Fig. 4D) . In contrast, DDX58, a gene downregulated by H5N1-VN1203 but not MERS-CoV, actually had reduced H3K27me3 association following MERS-CoV infection. Similar to previous reports (27), the activating histone mark was variable in uninduced SARS-CoV-infected samples at 12 hpi; however, a late time point (36 hpi) that corresponded with robust ISG expression demonstrated increased H3K4me3 and reduced H3K27me3 modifications relative to mock (see Fig. S4 in the supplemental material). Together, the data suggested that while the activating motif was less predictable, the dominant H3K27me3 repressive histone mark was associated only with ISGs downregulated by both MERS-CoV and H5N1-VN1203 (28) .