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.

Regulation. Previously, we demonstrated that a subset of type I ISGs are down-regulated by H5N1-VN1203 and MERS-CoV infections, and our results implicated alterations in histone modification in driving differential ISG expression (6) . To determine whether histone modifications also affect antigen-presentation gene expression, we examined enrichment of activating (H3K4me3) and repressive (H3K27me3) methylation markers on the 5′ promoters of MHC class I (HLA-A), II (HLA-DRB), and III (LTA) molecules in lysates from cells infected with SARS-CoV, MERS-CoV, H5N1-VN1203, or H1N1-09 using a chromatin immunoprecipitation-PCR (ChIP-PCR)based approach. For the activating histone marker (H3K4me3), enrichment was observed only in HLA-A promoter regions following H1N1-09 and H5N1-VN1203 infection, and no enrichment or loss of H3K4 trimethylation was observed for HLA-DRB1 or LTA promoters following either influenza virus infection (Fig. 4A ). SARS-CoV infections did not result in significant enrichment or loss of H3K4me3 for any of these genes. In contrast, MERS-CoV infection reduced H3K4 trimethylation for all three genes, with significant changes observed in HLA-DRB1 and LTA promoter regions. For all three promoter regions, strong reductions in the repressive marker (H3K27me3) were also observed following SARS-CoV and MERS-CoV infections (Fig. 4B) ; similarly, H1N1-09 and H5N1-VN1203 also reduced repressive marks for the HLA molecules. Together, the data suggest that modest transcriptional activation was possible if H3K4me3 motifs remained intact.