Impact of pregravid obesity on anti-microbial fetal monocyte response

Maternal pre-pregnancy (pregravid) obesity is associated with several adverse outcomes for both mother and offspring. Amongst the complications for the offspring is increased susceptibility and severity of neonatal infections necessitating admission to the intensive care unit, notably bacterial sepsis and enterocolitis. Previous studies have reported aberrant responses to LPS and polyclonal stimulation by umbilical cord blood monocytes and T cells respectively that were mediated by alterations in the epigenome of both cell types. In this study, we show that pregravid obesity dysregulates the umbilical cord blood monocyte response to bacterial and viral pathogens. Specifically, inflammatory responses and interferon stimulated gene expression to E. Coli and respiratory syncytial virus (RSV) were significantly dampened. Although upstream signaling events were comparable, translocation of key transcription factor NFkB and chromatin accessibility in promoters and regions that regulate the expression of anti-microbial genes was significantly reduced. Additional studies show that fetal peripheral blood mononuclear cells (PBMC) and tissue-resident macrophages obtained from rhesus macaques obtained from dams fed a western diet (high fat) chow generated a dampened response to LPS stimulation compared those obtained from control chow fed dams. Collectively, these data indicate that maternal obesity leads to a rewiring of the epigenome of fetal monocytes and tissue resident macrophages resulting in a state of immune paralysis at birth. Lean Cellplex oligos CMO301 CMO302 CMO303 CMO304 Obese Cellplex oligos CMO301 CMO302 CMO305 CMO306