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.

For viral antagonism, the epigenetic landscape represents a potent and important avenue to disrupt the host immune response (29) . While always a consideration for DNA viruses that reside in the nucleus, recent research has focused on how viruses utilize aspects of the epigenetic machinery to enable persistence and emergence (30) . In addition, several reports have highlighted how viruses have disrupted epigenetic regulation and impact the host immune response. For example, NS1 of influenza H3N2 has been implicated as a histone mimic disrupting the antiviral response (8) . Similarly, both hepatitis C virus and adenoviruses have proteins that interfere with epigenetics functions and alter global immune function (7, 31, 32) . Previous work by our group found clear association of repressive histone modification H3K27me3 with down-regulated ISGs following both MERS-CoV and H5N1-VN1203 infection (6); subsequently, despite pathway and transcription factor activation, the repressed state physically prevented transcription of these genes. Similarly, our results in this work argue that DNA methylation plays a similar role in the loss of antigen-presentation molecules following both MERS-CoV and H5N1-VN1203 infection. Importantly, the sequencing data suggest that other specific regions of the genome are also targeted by global methylation, potentially signifying critical pathways modulated by viral antagonism and providing a path for future studies. In addition, viruses may utilize distinct epigenetic mechanism in parallel, resulting in specific targeting of host ISGs by H3K27 trimethylation instead of DNA methylation within that genome region. Together, these results suggest that multiple viruses target different epigenetic processes to modulate aspects of host immunity and indicate that additional studies will be required to fully understand how epigenetics modulates the host immune response following virus infection.