Infant RSV immunoprophylaxis changes nasal epithelial DNA methylation at six years of age

BackgroundRespiratory syncytial virus (RSV) infection has been associated with childhood wheeze and asthma, and potential mechanisms include persistent epigenetic effects. MethodsIn the randomized, placebo-controlled MAKI trial, 429 preterm infants randomly received RSV immunoprophylaxis with palivizumab or placebo during their first RSV season. Children were followed until age 6 for asthma evaluation. DNA methylation in cells obtained by nasal brushes at age 6 was measured by Illumina MethylationEPIC array. ResultsRSV immunoprophylaxis in infancy had significant impact on global methylation patterns in nasal cells at age 6. The first 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, cg18040241, cg08243963, cg19555973 were differentially methylated at genome-wide significance, but 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. ConclusionsThe study provides the first proof of concept that RSV immunoprophylaxis during infancy has long-term effects on nasal epigenetic signatures at age 6, relating to host antiviral defense pathways.