# Respiratory Infection- and Asthma-prone, Low Vaccine Responder Children Demonstrate Distinct Mononuclear Cell DNA Methylation Pathways

## TL;DR

Children prone to infections and asthma show unique DNA methylation patterns that may help identify and treat immune issues early.

## Contribution

The study identifies distinct DNA methylation pathways in infection-prone children linked to immune and asthma-related processes.

## Key findings

- An endotype signature of 813 DMRs was found, linked to asthma and immune pathways.
- MPLA stimulation partially reversed methylation patterns, suggesting potential for immune modulation.
- Genetic variation explained only a small part of the methylation signature.

## Abstract

Infants with frequent viral and bacterial respiratory infections exhibit compromised immunity to routine immunisations. They are also more likely to develop chronic respiratory diseases in later childhood. This study investigated the feasibility of epigenetic profiling to reveal endotype-specific molecular pathways with potential for early identification and immuno-modulation. Peripharal immune cells from respiratory infection allergy/asthma prone (IAP) infants were retrospectively selected for genome-wide DNA methylation and single nucleotide polymorphism analysis. The IAP infants were enriched for the low vaccine responsiveness (LVR) phenotype (Fishers Exact p-value = 0.01).

An endotype signature of 813 differentially methylated regions (DMRs) comprising 238 lead CpG associations (FDR < 0.05) emerged, implicating pathways related to asthma, mucin production, antigen presentation and inflammasome activation. Allelic variation explained only a minor portion of this signature. Stimulation of mononuclear cells with monophosphoryl lipid A (MPLA), a TLR agonist, partially reversing this signature at a subset of CpGs, suggesting the potential for epigenetic remodelling.

This proof-of-concept study establishes a foundation for precision endotyping of IAP children and highlights the potential for immune modulation strategies using adjuvants for furture investigation.