Maternal obesity blunts antimicrobial responses in fetal monocytes
Suhas Sureshchandra,
Brianna M Doratt,
Norma Mendza,
Oleg Varlamov,
Monica Rincon,
Nicole E Marshall,
Ilhem Messaoudi
Affiliations
Suhas Sureshchandra
Institute for Immunology, University of California, Irvine, Irvine, United States; Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, United States
Norma Mendza
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
Oleg Varlamov
Division of Cardiometabolic Health, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States; Maternal-Fetal Medicine, Oregon Health & Science University, Portland, United States
Maternal pre-pregnancy (pregravid) obesity is associated with 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 that were mediated by alterations in the epigenome. In this study, we show that pregravid obesity dysregulates umbilical cord blood monocyte responses to bacterial and viral pathogens. Specifically, interferon-stimulated gene expression and inflammatory responses to respiratory syncytial virus (RSV) and E. coli were significantly dampened, respectively . Although upstream signaling events were comparable, translocation of the key transcription factor NF-κB and chromatin accessibility at pro-inflammatory gene promoters following TLR stimulation was significantly attenuated. Using a rhesus macaque model of western style diet-induced obesity, we further demonstrate that this defect is detected in fetal peripheral monocytes and tissue-resident macrophages during gestation. Collectively, these data indicate that maternal obesity alters metabolic, signaling, and epigenetic profiles of fetal monocytes leading to a state of immune paralysis during late gestation and at birth.
