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.

In addition to identifying differential ISG induction profiles, this study also introduces a novel avenue for viral antagonism of host gene expression via altered histone modification (Fig. 6) . A large number of host enzymes catalyze methylation and demethylation of histones, a process that is essential for regulating transcriptional programs (26, 34) . In particular, innate immune responses, including ISG responses, are highly regulated by epigenetic control mechanisms, including alteration of methylation and acylation patterns in chromatin (35, 36) . By catalyzing the placement or removal of histone methyl marks at H3K4 (transcriptionally active) and H3K27 (transcriptionally repressive), histone lysine methyltransferases (MLL2, MLL3, and EZH2) and demethylases (RBP2, UTX, and JMJD3) modify the chromatin state to maintain and fine-tune transcriptional control (26) . During H1N1-09 or SARS-CoV infection, the host cell recognizes the viruses, produces type I and type III IFN, and induces histone modulation complexes to remove the repressive histone marks (H3K27me3) and add activating modifications (H3K4me3); this process shifts targeted chromosomal locations to a more open, activated state and permits the binding of activated transcription factors like STAT1 and IRF7, allowing robust ISG expression. In contrast, during MERS-CoV and H5N1-VN1203 infection, some histones undergo the activating modifications resulting in robust expression of a subset of ISGs; however, for another subset of genes, chromatin remodeling complexes incorporate the repressive histone modification (H3K27me3) while also removing the active marker (H3K4me3), resulting in a condensed chromatin structure. This closed structure likely excludes transcription factors and reduces RNA expression of target ISGs. While differences in transcriptional factor phosphorylation state or binding sites may also contribute, the altered histone modification approach suppresses expression of target genes. While histone modification has been shown to play a role in a variety of host processes, including cell development (37) , host metabolism (38) , and ISG induction (36) , these findings represent additional evidence that pathogens can exploit the same repression processes to modulate and control the host IFN response (39, 40) ; similar modulation by pathogens likely impacts other critical host processes, including inflammation, antigen presentation, and aging (26, 34) . The presence of this antagonism in disparate, highly virulent respiratory pathogens not only supports earlier studies involving the H3N2 NS1 histone mimic (24) but also suggests that the approach may be conserved across multiple viral families and contribute to enhanced disease virulence. The large number of cellular proteins present within histone modification complexes potentially provides a rich diversity of targets for pathogen-coded control and manipulation (26) . Importantly, antagonizing histone regulation may also prove to be an important factor in the emergence of both H5N1-VN1203 and MERS-CoV; broad evolutionary conservation of both histone modifications and machinery suggests that host targets may be conserved across diverse species, potentially easing cross-species infection by modulation of the host response (41) . However, the effect may also be reducing transmission efficiency by removing portions of the adaption requirements for host shifting. Future studies explore avian-and bat-derived cells for conse