bims-reprim 2021-11-07 papers

Cell Rep Med. 2021 Oct 27. 100453

The systemic inflammatory landscape of COVID19 in pregnancy: Extensive serum proteomic profiling of mother-infant dyads with in-utero SARS-CoV-2.

While pregnancy increases the risk for severe COVID19, the clinical and immunological implications of COVID19 on maternal-fetal health remain unknown. Here, we present the clinical and immunological landscapes of 93 COVID19 mothers and 45 of their SARS-CoV-2-exposed infants through comprehensive serum proteomics profiling for >1400 cytokines of their peripheral and cord blood specimens. Prenatal SARS-CoV-2 infection triggers NF-κB-dependent proinflammatory immune activation. Pregnant women with severe COVID19 show increased inflammation and unique IFNλ antiviral signaling, with elevated levels of IFNL1 and IFNLR1. Furthermore, SARS-CoV-2 infection re-shapes maternal immunity at delivery altering the expression of pregnancy complication-associated cytokines, inducing MMP7, MDK, ESM1, and reducing BGN and CD209. Finally, COVID19-exposed infants exhibit induction of T cell-associated cytokines (IL33, NFATC3 and CCL21), while some undergo IL-1β/IL-18/CASP1 axis-driven neonatal respiratory distress despite birth at term. Our findings demonstrate COVID19-induced immune rewiring in both mothers and neonates, warranting long-term clinical follow-up to mitigate potential health risks.

Keywords: COVID19; COVID19-exposed infants; IFNλ signaling; mother-infant pairs; pregnancy; prenatal SARS-CoV-2 infection; serum proteomics

DOI: https://doi.org/10.1016/j.xcrm.2021.100453

Front Immunol. 2021 ;12 752660

Cytokine Patterns in Maternal Serum From First Trimester to Term and Beyond.

Anders Hagen Jarmund, Guro Fanneløb Giskeødegård, Mariell Ryssdal, Bjørg Steinkjer, Live Marie Tobiesen Stokkeland, Torfinn Støve Madssen, Signe Nilssen Stafne, Solhild Stridsklev, Trine Moholdt, Runa Heimstad, Eszter Vanky, Ann-Charlotte Iversen.

Pregnancy implies delicate immunological balance between two individuals, with constant changes and adaptions in response to maternal capacity and fetal demands. We performed cytokine profiling of 1149 longitudinal serum samples from 707 pregnant women to map immunological changes from first trimester to term and beyond. The serum levels of 22 cytokines and C-reactive protein (CRP) followed diverse but characteristic trajectories throughout pregnancy, consistent with staged immunological adaptions. Eotaxin showed a particularly robust decrease throughout pregnancy. A strong surge in cytokine levels developed when pregnancies progressed beyond term and the increase was amplified as labor approached. Maternal obesity, smoking and pregnancies with large fetuses showed sustained increase in distinct cytokines throughout pregnancy. Multiparous women had increased cytokine levels in the first trimester compared to nulliparous women with higher cytokine levels in the third trimester. Fetal sex affected first trimester cytokine levels with increased levels in pregnancies with a female fetus. These findings unravel important immunological dynamics of pregnancy, demonstrate how both maternal and fetal factors influence maternal systemic cytokines, and serve as a comprehensive reference for cytokine profiles in normal pregnancies.

Keywords: colony-stimulating factors; growth factors; inflammation; longitudinal cytokine profile; maternal response; multiplex; pregnancy; reproductive immunology

DOI: https://doi.org/10.3389/fimmu.2021.752660

Mol Cell. 2021 Nov 01. pii: S1097-2765(21)00842-X. [Epub ahead of print]

A multi-omic single-cell landscape of human gynecologic malignancies.

Matthew J Regner, Kamila Wisniewska, Susana Garcia-Recio, Aatish Thennavan, Raul Mendez-Giraldez, Venkat S Malladi, Gabrielle Hawkins, Joel S Parker, Charles M Perou, Victoria L Bae-Jump, Hector L Franco.

Deconvolution of regulatory mechanisms that drive transcriptional programs in cancer cells is key to understanding tumor biology. Herein, we present matched transcriptome (scRNA-seq) and chromatin accessibility (scATAC-seq) profiles at single-cell resolution from human ovarian and endometrial tumors processed immediately following surgical resection. This dataset reveals the complex cellular heterogeneity of these tumors and enabled us to quantitatively link variation in chromatin accessibility to gene expression. We show that malignant cells acquire previously unannotated regulatory elements to drive hallmark cancer pathways. Moreover, malignant cells from within the same patients show substantial variation in chromatin accessibility linked to transcriptional output, highlighting the importance of intratumoral heterogeneity. Finally, we infer the malignant cell type-specific activity of transcription factors. By defining the regulatory logic of cancer cells, this work reveals an important reliance on oncogenic regulatory elements and highlights the ability of matched scRNA-seq/scATAC-seq to uncover clinically relevant mechanisms of tumorigenesis in gynecologic cancers.

Keywords: chromatin accessibility; endometrial cancer; enhancer elements; gastro-intestinal stromal tumors; gene regulation; intratumoral heterogeneity; ovarian cancer; scATAC-seq; scRNA-seq; single-cell genomics

DOI: https://doi.org/10.1016/j.molcel.2021.10.013

J Perinat Med. 2021 Nov 01.

Enhanced S100B expression in T and B lymphocytes in spontaneous preterm birth and preeclampsia.

Mandy Busse, Markus Scharm, Anika Oettel, Anke Redlich, Serban-Dan Costa, Ana Claudia Zenclussen.

OBJECTIVES: S100B belongs to the family of danger signaling proteins. It is mainly expressed by glial-specific cells in the brain. However, S100B was also detected in other cell likewise immune cells. This molecule was suggested as biomarker for inflammation and fetal brain damage in spontaneous preterm birth (sPTB), preeclampsia (PE) and HELLP (hemolysis, elevated liver enzymes, and low platelet count).METHODS: The aim of our study was to determine the concentration of S100B in maternal and cord blood (CB) plasma and placenta supernatant as well as the expression of S100B in maternal and CB CD4+ T cells and CD19+ B cells in sPTB and patients delivering following PE/HELLP diagnosis compared to women delivering at term (TD). The S100B expression was further related to the birth weight in our study cohort.
RESULTS: S100B concentration was enhanced in maternal and CB plasma of sPTB and PE/HELLP patients and positively correlated with interleukin-6 (IL-6) levels. Increased S100B was also confirmed in CB of small-for-gestational-age (SGA) infants. S100B expression in maternal blood was elevated in CD4+ T cells of PE/HELLP patients and patients who gave birth to SGA newborns as well as in CD19+ B cells of sPTB and PE/HELLP patients and patients with SGA babies. In CB, the expression of S100B was increased in CD19+ B cells of sPTB, PE/HELLP and SGA babies.
CONCLUSIONS: Our results support the hypothesis that S100B expression is enhanced in inflammatory events associated with preterm birth and that S100B expression in immune cells is a relevant marker for inflammation during pregnancy complications.

Keywords: B cells; S100B; T cells; preterm birth

DOI: https://doi.org/10.1515/jpm-2021-0326

Nat Rev Immunol. 2021 Nov 05.

Foetal sex affects maternal and placental immune responses to SARS-CoV-2.

Alexandra Flemming.

DOI: https://doi.org/10.1038/s41577-021-00653-5

Nat Commun. 2021 Nov 01. 12(1): 6289

The composition of human vaginal microbiota transferred at birth affects offspring health in a mouse model.

Eldin Jašarević, Elizabeth M Hill, Patrick J Kane, Lindsay Rutt, Trevonn Gyles, Lillian Folts, Kylie D Rock, Christopher D Howard, Kathleen E Morrison, Jacques Ravel, Tracy L Bale.

Newborns are colonized by maternal microbiota that is essential for offspring health and development. The composition of these pioneer communities exhibits individual differences, but the importance of this early-life heterogeneity to health outcomes is not understood. Here we validate a human microbiota-associated model in which fetal mice are cesarean delivered and gavaged with defined human vaginal microbial communities. This model replicates the inoculation that occurs during vaginal birth and reveals lasting effects on offspring metabolism, immunity, and the brain in a community-specific manner. This microbial effect is amplified by prior gestation in a maternal obesogenic or vaginal dysbiotic environment where placental and fetal ileum development are altered, and an augmented immune response increases rates of offspring mortality. Collectively, we describe a translationally relevant model to examine the defined role of specific human microbial communities on offspring health outcomes, and demonstrate that the prenatal environment dramatically shapes the postnatal response to inoculation.

DOI: https://doi.org/10.1038/s41467-021-26634-9

JAMA Netw Open. 2021 11 01. 4(11): e2132563

Immune Response of Neonates Born to Mothers Infected With SARS-CoV-2.

Importance: Although several studies have provided information on short-term clinical outcomes in children with perinatal exposure to SARS-CoV-2, data on the immune response in the first months of life among newborns exposed to the virus in utero are lacking.Objective: To characterize systemic and mucosal antibody production during the first 2 months of life among infants who were born to mothers infected with SARS-CoV-2.
Design, Setting, and Participants: This prospective cohort study enrolled 28 pregnant women who tested positive for SARS-CoV-2 infection and who gave birth at Policlinico Umberto I in Rome, Italy, from November 2020 to May 2021, and their newborns. Maternal and neonatal systemic immune responses were investigated by detecting spike-specific antibodies in serum, and the mucosal immune response was assessed by measuring specific antibodies in maternal breastmilk and infant saliva 48 hours after delivery and 2 months later.
Exposures: Maternal infection with SARS-CoV-2 in late pregnancy.
Main Outcomes and Measures: The systemic immune response was evaluated by the detection of SARS-CoV-2 IgG and IgA antibodies and receptor binding domain-specific IgM antibodies in maternal and neonatal serum. The mucosal immune response was assessed by measuring spike-specific antibodies in breastmilk and in infant saliva, and the presence of antigen-antibody spike IgA immune complexes was investigated in breastmilk samples. All antibodies were detected using an enzyme-linked immunosorbent assay.
Results: In total, 28 mother-infant dyads (mean [SD] maternal age, 31.8 [6.4] years; mean [SD] gestational age, 38.1 [2.3] weeks; 18 [60%] male infants) were enrolled at delivery, and 21 dyads completed the study at 2 months' follow-up. Because maternal infection was recent in all cases, transplacental transfer of virus spike-specific IgG antibodies occurred in only 1 infant. One case of potential vertical transmission and 1 case of horizontal infection were observed. Virus spike protein-specific salivary IgA antibodies were significantly increased (P = .01) in infants fed breastmilk (0.99 arbitrary units [AU]; IQR, 0.39-1.68 AU) vs infants fed an exclusive formula diet (0.16 AU; IQR, 0.02-0.83 AU). Maternal milk contained IgA spike immune complexes at 48 hours (0.53 AU; IQR, 0.25-0.39 AU) and at 2 months (0.09 AU; IQR, 0.03-0.17 AU) and may have functioned as specific stimuli for the infant mucosal immune response.
Conclusions and Relevance: In this cohort study, SARS-CoV-2 spike-specific IgA antibodies were detected in infant saliva, which may partly explain why newborns are resistant to SARS-CoV-2 infection. Mothers infected in the peripartum period appear to not only passively protect the newborn via breastmilk secretory IgA but also actively stimulate and train the neonatal immune system via breastmilk immune complexes.

DOI: https://doi.org/10.1001/jamanetworkopen.2021.32563