Differential immunophenotype of circulating monocytes from pregnant women in response to viral ligands

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Abstract

Background

Viral infections during pregnancy can have deleterious effects on mothers and their offspring. Monocytes participate in the maternal host defense against invading viruses; however, whether pregnancy alters monocyte responses is still under investigation. Herein, we undertook a comprehensive in vitro study of peripheral monocytes to characterize the differences in phenotype and interferon release driven by viral ligands between pregnant and non-pregnant women.

Methods

Peripheral blood was collected from third-trimester pregnant ( n = 20) or non-pregnant ( n = 20, controls) women. Peripheral blood mononuclear cells were isolated and exposed to R848 (TLR7/TLR8 agonist), Gardiquimod (TLR7 agonist), Poly(I:C) (HMW) VacciGrade™ (TLR3 agonist), Poly(I:C) (HMW) LyoVec™ (RIG-I/MDA-5 agonist), or ODN2216 (TLR9 agonist) for 24 h. Cells and supernatants were collected for monocyte phenotyping and immunoassays to detect specific interferons, respectively.

Results

The proportions of classical (CD14 ^hiCD16 ⁻), intermediate (CD14 ^hiCD16 ⁺), non-classical (CD14 ^loCD16 ⁺), and CD14 ^loCD16 ⁻ monocytes were differentially affected between pregnant and non-pregnant women in response to TLR3 stimulation. The proportions of pregnancy-derived monocytes expressing adhesion molecules (Basigin and PSGL-1) or the chemokine receptors CCR5 and CCR2 were diminished in response to TLR7/TLR8 stimulation, while the proportions of CCR5 ⁻ monocytes were increased. Such differences were found to be primarily driven by TLR8 signaling, rather than TLR7. Moreover, the proportions of monocytes expressing the chemokine receptor CXCR1 were increased during pregnancy in response to poly(I:C) stimulation through TLR3, but not RIG-I/MDA-5. By contrast, pregnancy-specific changes in the monocyte response to TLR9 stimulation were not observed. Notably, the soluble interferon response to viral stimulation by mononuclear cells was not diminished in pregnancy.

Conclusions

Our data provide insight into the differential responsiveness of pregnancy-derived monocytes to ssRNA and dsRNA, mainly driven by TLR8 and membrane-bound TLR3, which may help to explain the increased susceptibility of pregnant women to adverse outcomes resulting from viral infection as observed during recent and historic pandemics.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12884-023-05562-0.

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Most cited references 121

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SARS-CoV-2 variants, spike mutations and immune escape

William T. Harvey, Alessandro M. Carabelli, Ben Jackson … (2021)

Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of ‘variants of concern’, that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets. The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been characterized by the emergence of mutations and so-called variants of concern that impact virus characteristics, including transmissibility and antigenicity. In this Review, members of the COVID-19 Genomics UK (COG-UK) Consortium and colleagues summarize mutations of the SARS-CoV-2 spike protein, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.

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Global causes of maternal death: a WHO systematic analysis.

Lale Say, Doris Chou, Alison Gemmill … (2014)

Data for the causes of maternal deaths are needed to inform policies to improve maternal health. We developed and analysed global, regional, and subregional estimates of the causes of maternal death during 2003-09, with a novel method, updating the previous WHO systematic review. We searched specialised and general bibliographic databases for articles published between between Jan 1, 2003, and Dec 31, 2012, for research data, with no language restrictions, and the WHO mortality database for vital registration data. On the basis of prespecified inclusion criteria, we analysed causes of maternal death from datasets. We aggregated country level estimates to report estimates of causes of death by Millennium Development Goal regions and worldwide, for main and subcauses of death categories with a Bayesian hierarchical model. We identified 23 eligible studies (published 2003-12). We included 417 datasets from 115 countries comprising 60 799 deaths in the analysis. About 73% (1 771 000 of 2 443 000) of all maternal deaths between 2003 and 2009 were due to direct obstetric causes and deaths due to indirect causes accounted for 27·5% (672 000, 95% UI 19·7-37·5) of all deaths. Haemorrhage accounted for 27·1% (661 000, 19·9-36·2), hypertensive disorders 14·0% (343 000, 11·1-17·4), and sepsis 10·7% (261 000, 5·9-18·6) of maternal deaths. The rest of deaths were due to abortion (7·9% [193 000], 4·7-13·2), embolism (3·2% [78 000], 1·8-5·5), and all other direct causes of death (9·6% [235 000], 6·5-14·3). Regional estimates varied substantially. Between 2003 and 2009, haemorrhage, hypertensive disorders, and sepsis were responsible for more than half of maternal deaths worldwide. More than a quarter of deaths were attributable to indirect causes. These analyses should inform the prioritisation of health policies, programmes, and funding to reduce maternal deaths at regional and global levels. Further efforts are needed to improve the availability and quality of data related to maternal mortality. © 2014 World Health Organization; licensee Elsevier. This is an Open Access article published without any waiver of WHO's privileges and immunities under international law, convention, or agreement. This article should not be reproduced for use in association with the promotion of commercial products, services, or any legal entity. There should be no suggestion that WHO endorses any specific organisation or products. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

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Circulating angiogenic factors and the risk of preeclampsia.

Richard J. Levine, Sharon E. Maynard, Cong Qian … (2004)

The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia. Copyright 2004 Massachusetts Medical Society

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Author and article information

Contributors

Nardhy Gomez-Lopez: nardhy.gomez-lopez@wayne.edu , ngomezlo@med.wayne.edu

Journal

Journal ID (nlm-ta): BMC Pregnancy Childbirth

Journal ID (iso-abbrev): BMC Pregnancy Childbirth

Title: BMC Pregnancy and Childbirth

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2393

Publication date (Electronic): 6 May 2023

Publication date PMC-release: 6 May 2023

Publication date Collection: 2023

Volume: 23

Electronic Location Identifier: 323

Affiliations

[1 ]Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Detroit, MI 48201 USA

[2 ]GRID grid.254444.7, ISNI 0000 0001 1456 7807, Department of Obstetrics and Gynecology, , Wayne State University School of Medicine, ; Detroit, Michigan, 48201 USA

[3 ]GRID grid.7870.8, ISNI 0000 0001 2157 0406, Division of Obstetrics and Gynecology, Faculty of Medicine, , Pontificia Universidad Católica de Chile, ; 8330024 Santiago, Chile

[4 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Obstetrics and Gynecology, , University of Michigan, ; Ann Arbor, MI 48109 USA

[5 ]GRID grid.17088.36, ISNI 0000 0001 2150 1785, Department of Epidemiology and Biostatistics, , Michigan State University, ; East Lansing, MI 48824 USA

[6 ]GRID grid.254444.7, ISNI 0000 0001 1456 7807, Wayne State University School of Medicine, ; Detroit, MI 48201 USA

[7 ]GRID grid.254444.7, ISNI 0000 0001 1456 7807, Department of Computer Science, , Wayne State University College of Engineering, ; Detroit, MI 48202 USA

[8 ]GRID grid.254444.7, ISNI 0000 0001 1456 7807, Center for Molecular Medicine and Genetics, , Wayne State University, ; Detroit, MI 48201 USA

[9 ]GRID grid.254444.7, ISNI 0000 0001 1456 7807, Department of Biochemistry, Microbiology, and Immunology, , Wayne State University School of Medicine, ; Detroit, MI 48201 USA

Article

Publisher ID: 5562

DOI: 10.1186/s12884-023-05562-0

PMC ID: 10163583

SO-VID: c7271cce-83e1-4a8d-b948-b5c4387a5a99

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 30 November 2022

Date accepted : 30 March 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009633, Eunice Kennedy Shriver National Institute of Child Health and Human Development;

Award ID: HHSN275201300006C

Award Recipient : Roberto Romero Adi L. Tarca Nardhy Gomez-Lopez

Funded by: Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health

Custom metadata

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: virus,innate immunity,infection,pregnancy,human

Data availability:

ScienceOpen disciplines: Obstetrics & Gynecology

Keywords: virus, innate immunity, infection, pregnancy, human

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