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.

System-based analysis has previously revealed similarities and contrasts in terms of ISG induction between and within viral families (6) . This study extends that approach, demonstrating DE of IFN-γ-dependent genes following H1N1-09, H5N1-VN1203, SARS-CoV, and MERS-CoV infection. Expanding on the initial comparison, analysis of functional categories demonstrated global down-regulation of MHC and antigen-presentation molecules following both MERS-CoV and H5N1-VN1203 infection; these results correspond to MHC down-regulation reported for H5N1 in A549 and chicken embryonic fibroblasts (16, 17) . The changes in RNA expression were found throughout the MHC locus and were confirmed by proteomic analysis in both viruses. Seeking mechanistic insights, epigenetic studies captured robust increases in DNA methylation following MERS-CoV infection with no similar trend observed following mock or SARS-CoV infection. However, while H5N1-VN1203 had augmented DNA methylation relative to mock, its overall increase was less uniform than MERS-CoV, leaving the possibility that histone modification may also contribute to control of antigen-presentation gene expression. Together, the data from both MERS-CoV and H5N1-VN1203 infection suggest that multiple epigenetic mechanisms contribute to antagonism of the host immune response.