Cross-Cohort Integration of Blood DNA Methylation and Sepsis Transcriptomes Prioritizes TP53INP1 as a Candidate Associated with B-Cell Transcriptomic Patterns in Pediatric HAdV-7-Associated Sepsis

Abstract

Human adenovirus type 7 (HAdV-7) can cause severe pneumonia and sepsis in children, but the associated host epigenetic and immune alterations remain poorly defined. We profiled peripheral-blood DNA methylation in 11 children with HAdV-7-associated sepsis (6 survivors and 5 non-survivors) and 5 pediatric controls without clinically detectable HAdV-7 infection using reduced representation bisulfite sequencing. Differentially methylated genes were integrated with pediatric septic shock transcriptomic modules from GSE26440, and their cellular distribution and predicted regulatory effects were explored using the single-cell dataset GSE167363 and scTenifoldKnk. We identified 106 genes showing differential methylation across all three pairwise comparisons. Cross-cohort integration prioritized 19 candidate genes, among which TP53INP1 showed preferential expression in B cells in the external sepsis single-cell dataset. In silico perturbation of TP53INP1 was associated with changes in interferon-stimulated and antiviral genes, including TRIM22, IFI44L, and PARP14. These findings identify TP53INP1 as a hypothesis-generating candidate linking HAdV-7-associated whole-blood methylation changes with B-cell regulatory networks observed in an external sepsis dataset. Given the small discovery cohort and absence of experimental validation, the findings are exploratory and require confirmation in independent cohorts.