Rhinovirus infections change DNA methylation and mRNA expression in children with asthma

PLoS One. 2018 Nov 28;13(11):e0205275. doi: 10.1371/journal.pone.0205275. eCollection 2018.

Abstract

Human rhinovirus infection (HRVI) plays an important role in asthma exacerbations and is thought to be involved in asthma development during early childhood. We hypothesized that HRVI causes differential DNA methylation and subsequently differential mRNA expression in epithelial cells of children with asthma. Primary nasal epithelial cells from children with (n = 10) and without (n = 10) asthma were cultivated up to passage two and infected with Rhinovirus-16 (RV-16). HRVI-induced genome-wide differences of DNA methylation in asthmatics (vs. controls) and resulting mRNA expression were analyzed by the HumanMethylation450 BeadChip Kit (Illumina) and RNA sequencing. These results were further verified by pyrosequencing and quantitative PCR, respectively. 471 CpGs belonging to 268 genes were identified to have HRVI-induced asthma-specifically modified DNA methylation and mRNA expression. A minimum-change criteria was applied to restrict assessment of genes with changes in DNA methylation and mRNA expression of at least 3% and least 0.1 reads/kb per million mapped reads, respectively. Using this approach we identified 16 CpGs, including HLA-B-associated transcript 3 (BAT3) and Neuraminidase 1 (NEU1), involved in host immune response against HRVI. HRVI in nasal epithelial cells leads to specific modifications of DNA methylation with altered mRNA expression in children with asthma. The HRVI-induced alterations in DNA methylation occurred in genes involved in the host immune response against viral infections and asthma pathogenesis. The findings of our pilot study may partially explain how HRVI contribute to the persistence and progression of asthma, and aid to identify possible new therapeutic targets. The promising findings of this pilot study would benefit from replication in a larger cohort.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Asthma / genetics*
  • Asthma / virology*
  • Biomarkers / metabolism
  • Case-Control Studies
  • Chemokine CCL5 / genetics
  • Chemokine CCL5 / metabolism
  • Child
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Down-Regulation / genetics
  • Epithelial Cells / pathology
  • Epithelial Cells / virology
  • Female
  • Gene Expression Regulation*
  • Humans
  • Male
  • Models, Biological
  • Nasal Mucosa / pathology
  • Picornaviridae Infections / genetics*
  • Picornaviridae Infections / virology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Rhinovirus / physiology*
  • Up-Regulation / genetics

Substances

  • Biomarkers
  • CCL5 protein, human
  • Chemokine CCL5
  • RNA, Messenger

Grant support

This research was supported by the German Center of Lung Research (DZL) grant number:82DZL00106; https://www.dzl.de/index.php/en/research/disease-areas/asthma-and-allergy). Funders had no role in any of the experimental work or publication.