MERS-CoV and H5N1 influenza virus antagonize antigen presentation by altering the epigenetic landscape

Menachery, Vineet D.; Schäfer, Alexandra; Burnum-Johnson, Kristin E.; Mitchell, Hugh D.; Eisfeld, Amie J.; Walters, Kevin B.; Nicora, Carrie D.; Purvine, Samuel O.; Casey, Cameron P.; Monroe, Matthew E.; Weitz, Karl K.; Stratton, Kelly G.; Webb-Robertson, Bobbie-Jo M.; Gralinski, Lisa E.; Metz, Thomas O.; Smith, Richard D.; Waters, Katrina M.; Sims, Amy C.; Kawaoka, Yoshihiro; Baric, Ralph S.

In this study, we expanded upon our previous approach to explore IFN-γ-dependent gene expression following pathogenic influenza and CoV infection (6) . Dividing differentially expressed genes by function, we observed down-regulation of IFNγ-associated antigen-presentation gene expression following both H5N1-VN1203 and MERS-CoV infection. When all major histocompatibility complex (MHC) molecules and antigenpresentation genes were considered, the data demonstrated global down-regulation of gene expression that was confirmed by proteomic analysis. However, in contrast to the mechanisms controlling ISG expression (6), analysis of histone modifications did not reveal Increases in either activating or repressive markers following MERS-CoV infection. Instead, changes in DNA methylation likely facilitate MERS-CoV-mediated down-regulation of antigen-presentation molecules. For H5N1-VN1203, both histone modification and DNA methylation may play a role through the activity of viral NS1. In contrast, MERS-CoV accessory ORF mutants maintain gene expression down-regulation despite robust attenuation in virus growth. Together, these results highlight epigenetic modification as an important means by which respiratory viruses modulate host immunity.