Maternal obesity blunts antimicrobial responses in fetal monocytes

Area of Science:

• Immunology
• Developmental Biology
• Metabolic Disorders

Background:

• Maternal obesity is linked to adverse pregnancy outcomes and increased neonatal infection risk.
• Previous research suggests epigenetic alterations in fetal monocytes contribute to aberrant immune responses.
• Neonatal infections, such as sepsis and enterocolitis, are significant causes of infant morbidity and mortality.

Purpose of the Study:

• To investigate the impact of maternal pre-pregnancy obesity on fetal monocyte immune responses to pathogens.
• To identify specific immune signaling and epigenetic dysregulations in fetal monocytes due to maternal obesity.
• To validate findings in a relevant animal model of diet-induced obesity.

Main Methods:

• Analysis of umbilical cord blood monocyte responses to respiratory syncytial virus (RSV) and Escherichia coli (E. coli).
• Assessment of NF-κB translocation and chromatin accessibility at pro-inflammatory gene promoters.
• Utilizing a rhesus macaque model to study diet-induced obesity and its effects on fetal immune cells.

Main Results:

• Maternal obesity significantly dampened interferon-stimulated gene expression in response to RSV and inflammatory responses to E. coli.
• NF-κB translocation and chromatin accessibility were attenuated following Toll-like receptor (TLR) stimulation.
• Immune defects were observed in fetal peripheral monocytes and tissue-resident macrophages in obese macaques.

Conclusions:

• Maternal obesity induces immune paralysis in fetal monocytes, characterized by dampened responses to bacterial and viral pathogens.
• Epigenetic dysregulation and impaired signaling contribute to the compromised immune function of fetal monocytes.
• These findings highlight a critical window during gestation where maternal metabolic status profoundly impacts offspring immunity, increasing neonatal infection susceptibility.