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The response to influenza vaccination is associated with DNA methylation-driven regulation of T cell innate antiviral pathways

ABSTRACT: The effect of vaccination on the epigenome remains poorly characterized. In previous research, we identified an association between seroprotection against influenza and DNA methylation at sites associated with the RIG-1 signaling pathway, which recognizes viral double-stranded RNA and leads to a type I interferon response. However, these studies did not fully account for confounding factors including age, gender, and BMI, along with changes in cell type composition. Here, we studied the influenza vaccine response in a longitudinal cohort vaccinated over two consecutive years (2019–2020 and 2020–2021), using peripheral blood mononuclear cells and a targeted DNA methylation approach. To address the effects of multiple factors on the epigenome, we designed a multivariate multiple regression model that included seroprotection levels as quantified by the hemagglutination-inhibition (HAI) assay test. Our findings indicate that 179 methylation sites can be combined as potential signatures to predict seroprotection. These sites were not only enriched for genes involved in the regulation of the RIG-I signaling pathway, as found previously, but also enriched for other genes associated with innate immunity to viruses and the transcription factor binding sites of BRD4, which is known to impact T cell memory. We propose a model to suggest that the RIG-I pathway and BRD4 could potentially be modulated to improve immunization strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263782 | GEO | 2024/06/12

REPOSITORIES: GEO

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Project description:The purpose of the study was to assess the patterns of global gene expression in peripheral blood cells and uncover the complex dynamics of host response to ARIs such as pandemic H1N1. To understand the molecular bases and network orchestration of host responses, we prospectively enrolled 1610 healthy adults in the fall of 2009 and 2010, followed the subjects with influenza-like illness (N=133) for 3 weeks, and examined changes in their peripheral blood gene expression. We discovered distinct phases of the host response spanning 6 days after infection, and identified genes that differentiate influenza from non-influenza virus infection. We examined pre- and post-infection anti-influenza antibody titers defining novel gene expression correlates. Healthy adults were invited to enroll to be followed for acute respiratory illness (ARI) through two consecutive influenza seasons 2009-2010 and 2010-2011. After subjects provided consent, baseline blood specimens were obtained during enrollment. Subjects were given thermometers and instructions to call and report for evaluation within 48 hours of ARI onset. Those persons who had a new ARI were seen within 48 hours of onset (day 0) and 2, 4, and 6 days later for repeat evaluation, blood specimen collections, and medical care (including the antiviral zanamivir if indicated) and 21 days later for collection of convalescent specimens. Nasal wash samples were collected for virus detection by RT-PCR on day 0 and day 2. Surveillance for influenza was terminated after 5.5 months; all subjects were asked to return for specimen collection and to provide a medical and ARI history in spring of next year. Serum specimens obtained at baseline, day 0 and day 21 visits for illnesses, and the terminal visit were tested simultaneously using hemagglutination-inhibition (HAI) antibody assay for Influenza H1N1, H3N2, and Influenza B strains. Peripheral blood RNA (PaxGene) obtained from blood specimens at each visit were analyzed using Illumina Human HT-12 v4. The study was repeated 2010-2011. A total of 880 arrays, corresponding to 133 individuals, passed quality control and are included in this data set.

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The response to influenza vaccination is associated with DNA methylation-driven regulation of T cell innate antiviral pathways

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