Longitudinal analysis of influenza vaccination implicates regulation of RIG-I signaling by DNA methylation

Abstract

Influenza virus infection alters the promoter DNA methylation of key immune response-related genes, including type-1 interferons and proinflammatory cytokines. However, less is known about the effect of the influenza vaccine on the epigenome. We utilized a targeted DNA methylation approach to study the longitudinal effects (day 0 pre-vaccination and day 28 post-vaccination) on influenza vaccination responses in peripheral blood mononuclear cells. We found that baseline, pre-vaccination methylation profiles are associated with pre-existing, protective serological immunity. Additionally, we identified 481 sites that were differentially methylated between baseline and day 28 post-vaccination. These were enriched for genes involved in the regulation of the RIG-I signaling pathway, an important regulator of viral responses. Our results suggest that DNA methylation changes to components of the RIG-I pathway are associated with vaccine effectiveness. Therefore, immunization strategies that target this pathway may improve serological responses to influenza vaccination.

Longitudinal assessment of human antibody binding to hemagglutinin elicited by split-inactivated influenza vaccination over six consecutive seasons

“…In order to fully understand the host influences on vaccination and the ever-changing influenza variants over time, samples from these cohorts have been analyzed for host RNA gene expression profiles by transcriptomics [ 59 ], host glycomics [ 60 ], proteomics [ 61 ], and metabolomics [ 62 ], as well as DNA methylation and immune senescence [ 63 ]. These data sets have been used to develop predictive models of host responses and vaccine effectiveness [ 64 ].…”

Cellular and Molecular Immunity to Influenza Viruses and Vaccines

“…In terms of CD4 + T cells this signifies skewing from a Th1 inflammatory response to a Th2 noninflammatory response. Another recent study concerning the flu vaccine studied DNA methylation patterns in a longitudinal analysis of yearly vaccinations [127]. In this study it was found that repeated vaccinations lead to DNA methylation primarily of genes associated with the signaling pathway for the pattern recognition receptor RIG-1, retinoic-acid-inducible gene-1.…”

“…The outcome of increased RIG-1 activity was an increase in transcription of type 1 IFNs (α/ß). Analysis of the cells associated with the repeated flu vaccinations has shown that mast cells are involved in some way [127]. A ligand for RIG-1 is 5' ppp-dsRNA and it has been found that incorporation of this ligand, as an adjuvant, with a flu vaccine markedly increased the generation of neutralizing high affinity antibodies in mice [128].…”

Cellular and Molecular Immunity to Influenza Viruses and Vaccines

“…In terms of CD4 + T cells, this signifies skewing from a Th1 inflammatory response to a Th2 noninflammatory response. Another recent study concerning the flu vaccine studied DNA methylation patterns in a longitudinal analysis of yearly vaccinations [ 126 ]. In this study, it was found that repeated vaccinations lead to DNA methylation, primarily of genes associated with the signaling pathway for the pattern recognition receptor RIG-1, retinoic-acid-inducible gene-1.…”

“…The outcome of increased RIG-1 activity was an increase in transcription of type 1 IFNs (α/ß). Analysis of the cells associated with the repeated flu vaccinations has shown that mast cells are involved in some way [ 126 ]. A ligand for RIG-1 is 5’ ppp-dsRNA, and it has been found that incorporation of this ligand, as an adjuvant, with a flu vaccine markedly increased the generation of neutralizing high affinity antibodies in mice [ 127 ].…”