Infant RSV infection changes nasal epithelial DNA methylation at 6 years of age

Objective: Respiratory syncytial virus (RSV) infection has been associated with childhood wheeze and asthma development, and potential mechanisms include persistent epigenetic effects. This study is to understand the link between RSV immunoprophylaxis with palivizumab, DNA methylation changes, and asthma development. Methods: In the randomized, placebo-controlled MAKI trial, 332 preterm infants randomly received RSV immunoprophylaxis with palivizumab or placebo during their first RSV season. Children were followed until age 6 for asthma evaluation. We used Illumina MethylationEPIC array to measure DNA methylation in the nasal epithelium at age 6. Results: RSV immunoprophylaxis in infancy had significant impact on methylation patterns in the nasal epithelium at age 6 (Overall methylation differences P=0.0055). The principal component related to the immunoprophylaxis intervention was enriched for the pathway “positive regulation of defense response to virus by host” and “antigen processing and presentation” and driven by methylation changes in NOD2, DGKG, MSH3, and ITPR2. Three CpGsites in cg18040241, cg08243963, cg19555973 were differentially methylated at genome-wide significance. These CpGsites were not associated with asthma. Differential methylation region analysis identified regions near genes that were previously implicated in the development of asthma and allergy such as HLA-DPA1, HLA-DPB1, FASLG, and CHI3L1. Conclusions: The study shows that RSV infection during infancy has a long-term effect on nasal epigenetic signatures at age 6. We conclude that early life respiratory infections may have persistent effects on gene function in host antiviral defense pathways. Funding: MedImmune grant ESR-14-10006