Biology subjects

Marshall, N. E.

Publications and source records attributed to Marshall, N. E..

7 recordsLinked to original sources

bioRxiv2025

Differential activation of p53-Lamin A/C and p16-RB mediated senescence pathways in trophoblast from pregnancies complicated by type A2 Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) increases maternal risks such as hypertension and future type 2 diabetes while also contributing to fetal complications such as large-for-gestational-age infants and stillbirth. The placenta which is crucial for fetal development, exhibits structural and functional changes in GDM, but the impact of these alterations on placental trophoblast function remains unclear. During their differentiation villous cytotrophoblast display several characteristics of senescent cells however the role of senescence pathways in placental function remains unexplored in GDM. Here we investigate whether placental senescence pathways are altered in GDM, utilizing term villous tissue and primary trophoblasts to assess molecular changes, and determined fetal sex-based differences. Our data suggest that both p21 and p16 mediated senescence pathways are activated during trophoblast differentiation and are dysregulated in GDM placenta in a sexually dimorphic manner. We also provide evidence for increased activation of p53-Lamin A/C and p16-RB pathways in trophoblast from GDM placentas. Reduced expression of p21 and its downstream effects on GCM1 expression and {beta}hCG secretion outline how altered physiological senescence can affect trophoblast differentiation and function. This is a seminal study highlighting how placental senescence pathways are altered in pregnancies complicated by GDM.

cell biology↗

bioRxiv2023

Mild/Asymptomatic Maternal SARS-CoV-2 Infection Leads to Immune Paralysis in Fetal Circulation and Immune Dysregulation in Fetal-Placental Tissues

Few studies have addressed the impact of maternal mild/asymptomatic SARS-CoV-2 infection on the developing neonatal immune system. In this study, we analyzed umbilical cord blood and placental chorionic villi from newborns of unvaccinated mothers with mild/asymptomatic SARS-CoV-2 infection during pregnancy using flow cytometry, single-cell transcriptomics, and functional assays. Despite the lack of vertical transmission, levels of inflammatory mediators were altered in cord blood. Maternal infection was also associated with increased memory T, B cells, and non-classical monocytes as well as increased activation. However, ex vivo responses to stimulation were attenuated. Finally, within the placental villi, we report an expansion of fetal Hofbauer cells and infiltrating maternal macrophages and rewiring towards a heightened inflammatory state. In contrast to cord blood monocytes, placental myeloid cells were primed for heightened antiviral responses. Taken together, this study highlights dysregulated fetal immune cell responses in response to mild maternal SARS-CoV-2 infection during pregnancy.

immunology↗

bioRxiv2022

SARS-CoV-2 Vaccine Booster Elicits Robust Prolonged Maternal Antibody Responses and Passive Transfer Via The Placenta And Breastmilk

BackgroundInfection during pregnancy can result in adverse outcomes for both pregnant persons and offspring. Maternal vaccination is an effective mechanism to protect both mother and neonate into post-partum. However, our understanding of passive transfer of antibodies elicited by maternal SARS-CoV-2 mRNA vaccination during pregnancy remains incomplete. ObjectiveWe aimed to evaluate the antibody responses engendered by maternal SARS-CoV-2 vaccination following initial and booster doses in maternal circulation and breastmilk to better understand passive immunization of the newborn. Study DesignWe collected longitudinal blood samples from 121 pregnant women who received SARS-CoV-2 mRNA vaccines spanning from early gestation to delivery followed by collection of blood samples and breastmilk between delivery and 12 months post-partum. During the study, 70% of the participants also received a booster post-partum. Paired maternal plasma, breastmilk, umbilical cord plasma, and newborn plasma samples were tested via enzyme-linked immunosorbent assays (ELISA) to evaluate SARS-CoV-2 specific IgG antibody levels. ResultsVaccine-elicited maternal antibodies were detected in both cord blood and newborn blood, albeit at lower levels than maternal circulation, demonstrating transplacental passive immunization. Booster vaccination significantly increased spike specific IgG antibody titers in maternal plasma and breastmilk. Finally, SARS-CoV-2 specific IgG antibodies in newborn blood correlated negatively with days post initial maternal vaccine dose. ConclusionVaccine-induced maternal SARS-CoV-2 antibodies were passively transferred to the offspring in utero via the placenta and after birth via breastfeeding. Maternal booster vaccination, regardless of gestational age at maternal vaccination, significantly increased antibody levels in breastmilk and maternal plasma, indicating the importance of this additional dose to maximize passive protection against SARS-CoV-2 infection for neonates and infants until vaccination eligibility.

immunology↗

bioRxiv2022

Multimodal profiling of term human decidua reveals tissue-specific immune adaptations with maternal obesity

The leukocyte diversity of early maternal-fetal interface has been recently described, however, characterization of decidua at term is still pending. We, therefore, profiled the CD45+ compartment within human term decidua collected via cesarean section. Relative to the first trimester, our analyses revealed a shift from NK cells and macrophages to T-cells and enhanced activation of all immune cells. T-cells in the decidua were phenotypically distinct from their blood counterparts and demonstrated significant clonotype sharing. Using pseudo-temporal analyses of macrophages, we characterize previously undescribed diversity of bonafide tissue resident decidual macrophages. The frequency of this population correlated with high pregravid maternal body mass index but responded poorly to bacteria ligands. Collectively, these findings provide evidence of skewing of decidual myeloid cells towards immunoregulation representing a possible mechanism to safeguard the fetus. This immune cell atlas of term decidua is an asset for future studies investigating pathological conditions that compromise reproductive success. One sentence summaryHuman immune cell atlas of term decidua and observed alterations with pre-gravid obesity.

immunology↗

bioRxiv2022

Impact of pregravid obesity on anti-microbial fetal monocyte response

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 E. coli and respiratory syncytial virus (RSV) were significantly dampened. Although upstream signaling events were comparable, translocation of the key transcription factor NF-{kappa}B 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 and high-fat diet present metabolic, signaling, and epigenetic impediments to pathogen recognition in fetal innate immune cells that result in a state of immune paralysis during gestation and at birth.

immunology↗

bioRxiv2021

Deep immune profiling of the maternal-fetal interface with mild SARS-CoV-2 infection

Pregnant women are an at-risk group for severe COVID-19, though the majority experience mild/asymptomatic disease. Although severe COVID-19 has been shown to be associated with immune activation at the maternal-fetal interface even in the absence of active viral replication, the immune response to asymptomatic/mild COVID-19 remains unknown. Here, we assessed immunological adaptations in both blood and term decidua from 9 SARS-exposed pregnant women with asymptomatic/mild disease and 15 pregnant SARS-naive women. In addition to selective loss of tissue-resident decidual macrophages, we report attenuation of antigen presentation and type I IFN signaling but upregulation of inflammatory cytokines and chemokines in blood monocyte derived decidual macrophages. On the other hand, infection was associated with remodeling of the T cell compartment with increased frequencies of activated CD69+ tissue-resident T cells and decreased abundance of Tregs. Interestingly, frequencies of cytotoxic CD4 and CD8 T cells increased only in the blood, while CD8 effector memory T cells were expanded in the decidua. In contrast to decidual macrophages, signatures of type I IFN signaling were increased in decidual T cells. Finally, T cell receptor diversity was significantly reduced with infection in both compartments, albeit to a much greater extent in the blood. The resulting aberrant immune activation in the placenta, even with asymptomatic disease may alter the exquisitely sensitive developing fetal immune system, leading to long-term adverse outcomes for offspring.

immunology↗

bioRxiv2020

Functional and genomic adaptations of blood monocytes to pregravid obesity during pregnancy

Pre-pregnancy obesity is associated with several adverse maternal health outcomes, notably increased risk of infection as well as the incidence of gestational diabetes, preeclampsia, and preterm birth. However, the mechanisms by which pregravid obesity disrupts the pregnancy associated "immune clock" are still unknown. To address this question, we collected blood samples from women during the first and third trimesters and determined the impact of both pregnancy and pregravid obesity on circulating immune mediators, immune cell subset frequencies, and peripheral immune responses. While regardless of BMI, pregnancy was associated with an elevation in both Th1 and Th2 cytokines, pregravid obesity was associated with a dysregulation in circulating myeloid factors at term. Moreover, pregnancy in lean subjects was associated with enhanced monocyte activation, augmented chromatin accessibility at inflammatory loci, and heightened responses to LPS. Pregravid obesity disrupted this trajectory and was accompanied by a lack of transcriptional and epigenetic changes and alterations in metabolic status strongly suggesting a skewing towards immunotolerance. These findings provide novel insight into the increased susceptibility to infections observed with obesity during pregnancy. SUMMARYA healthy pregnancy is associated with progressive innate immune activation. Maternal factors such as obesity compromise this myeloid cell activation trajectory at genomic, epigenomic, functional, and metabolic levels, resulting in stagnant immune responses, suggestive of a state of tolerance.

immunology↗