Biology subjects

Bacharier, L. B.

Publications and source records attributed to Bacharier, L. B..

3 recordsLinked to original sources

bioRxiv2024

Impact of early-life respiratory syncytial virus infection on cell type-specific airway DNA methylation

RationaleInfection with respiratory syncytial virus (RSV) in early-life is associated with subsequent childhood respiratory disorders, but the mechanism for this association is unknown. We hypothesized that RSV-mediated alteration in airway DNA methylation (DNAm) may play a role. ObjectivesInvestigate the impact of early-life RSV infection on airway DNAm. MethodsOur study population consisted of children from the INSPIRE population-based birth cohort. Early-life infection with RSV was defined as infection not requiring clinical illness before age one year, ascertained through active and passive surveillance. Methylation was measured in DNA from nasal airway epithelial cells (NAECs) at ages two years (n=88) and six years (n=539). Bulk gene expression in NAECs was available in a subset of participants at age two years (n=54). In silico cell type deconvolution was used to infer cell type-specific associations in suprabasal, ciliated, and "other" cell types. Measurements and Main ResultsWe identified 164 CpGs in ciliated cells and seven CpGs in suprabasal cells whose cell type-specific DNAm at age two years was associated with early-life RSV infection. The seven associations in suprabasal cells were still present at age six years and the directions of association replicated in in vitro infection of epithelial cells with RSV in air liquid interface cultures. DNAm levels at four of the seven CpGs identified in suprabasal cells correlated with the expression of their nearest genes in suprabasal cells, which included genes previously implicated in asthma-related diseases. The DNAm levels of these four CpGs and the expression of their nearest genes in suprabasal cells at age two years were also associated with recurrent wheezing at age four years. ConclusionsWe demonstrate epigenetic changes in airway progenitor cells of children who have had RSV infection in the first year of life are conserved over time, associated with subsequent wheeze, have functional relevance, and replicate in in vitro infection in ALI cultures. Our study is the first to show that early-life RSV infection, as opposed to severe illness, alters DNAm levels at functionally and clinically relevant loci.

genomics↗

bioRxiv2023

The gut metagenome harbors metabolic and antibiotic resistance signatures of moderate-to-severe asthma

Asthma is a common allergic airway disease that develops in association with the human microbiome early in life. Both the composition and function of the infant gut microbiota have been linked to asthma risk, but functional alterations in the gut microbiota of older patients with established asthma remain an important knowledge gap. Here, we performed whole metagenomic shotgun sequencing of 95 stool samples from 59 healthy and 36 subjects with moderate-to-severe asthma to characterize the metagenomes of gut microbiota in children and adults 6 years and older. Mapping of functional orthologs revealed that asthma contributes to 2.9% of the variation in metagenomic content even when accounting for other important clinical demographics. Differential abundance analysis showed an enrichment of long-chain fatty acid (LCFA) metabolism pathways which have been previously implicated in airway smooth muscle and immune responses in asthma. We also observed increased richness of antibiotic resistance genes (ARGs) in people with asthma. One differentially abundant ARG was a macrolide resistance marker, ermF, which significantly co-occurred with the Bacteroides fragilis toxin, suggesting a possible relationship between enterotoxigenic B. fragilis, antibiotic resistance, and asthma. Lastly, we found multiple virulence factor (VF) and ARG pairs that co-occurred in both cohorts suggesting that virulence and antibiotic resistance traits are co-selected and maintained in the fecal microbiota of people with asthma. Overall, our results show functional alterations via LCFA biosynthetic genes and increases in antibiotic resistance genes in the gut microbiota of subjects with moderate-to-severe asthma and could have implications for asthma management and treatment.

genomics↗

bioRxiv2022

The asthma gut microbiota influences lung inflammation in gnotobiotic mice

The composition of the gut microbiota in early childhood is linked to asthma risk but the role of the gut microbiota in older patients with established asthma is less clear. Here, we used a cohort of 38 school-aged children (19 with asthma) and 57 adults (17 with asthma) to develop a model that aids in the design of mechanistic experiments in gnotobiotic mice. These experiments show that enterotoxigenic Bacteroides fragilis (ETBF) is associated with increased gut permeability, oxidative stress, and markers of Th17-mediated inflammation in the lungs of mice following ovalbumin sensitization and challenge (OSC). Further, ETBF is enriched in a human population with asthma compared to healthy controls. Our results provide evidence that ETBF has the potential to alter the phenotype of airway inflammation in a subset of patients with asthma outside of early childhood which suggests that therapies targeting the gut microbiota may be helpful tools for asthma control.

microbiology↗