DNA methylation and gene expression signatures for common childhood infections

BACKGROUND: Early life exposure to common pathogens and a high pathogen burden during childhood can have long-term effects on immune development and overall health. These infections can trigger molecular changes, including alterations in gene expression and DNA methylation (DNAm), which regulate immune and metabolic pathways. Our aim was to identify biological processes underlying differential patterns of DNAm and gene expression in whole blood by infection status in European children. RESULTS: In the Rhea (Greece) and INMA (Spain) cohorts, serum/plasma samples collected at mean ages of 4 and 8 years were analyzed by multiplex serology to measure IgG against 14 antigens from 9 pathogens, and blood collected at a mean age of 8 years was used for DNAm and gene expression profiling. Epigenome- and transcriptome-wide analyses were conducted to assess association with childhood infections. A total of 290 unique CpGs were significantly associated with pathogen outcomes: 265 with seropositivity, 111 with first exposure timing, and one with viral burden. Cytomegalovirus (CMV) exposure accounted for the largest number of both epigenetic (n = 325) and transcriptomic (n = 8) associations. A total of 89 CMV-related CpGs had been described before in adults, and among novel ones, 54 showed consistent effects in adults. CMV-related CpGs were enriched for SUZ12 targets linked to morphogenesis, oxidative stress, and cognition. A previously developed CMV episcore in adults predicted serologically assessed CMV infection at 4 and 8 years of age, with area under the curve values ranging from 0.74 to 0.78 (95% CI 0.68-0.83). CONCLUSIONS: We identified novel DNAm and gene expression signatures of common childhood infections, particularly CMV, implicating immune and morphogenesis pathways. A subset of CMV-related DNAm signals showed consistent associations with those reported previously in adults, suggesting similar molecular effects across ages.