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  • Review Article
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Innate immune responses to pathogens at the maternal–fetal interface

Abstract

During pregnancy, the maternal immune system must navigate a balance between fetal tolerance and a response to acquired microbial infections. Cells at the maternal–fetal interface coordinate this response throughout gestational stages in a dynamic manner, integrating endocrine, developmental, inflammatory and metabolic cues. Although many maternal and fetal cell types activate innate immune signalling pathways in response to infections, excessive inflammation can disrupt tolerance, affect placental function and impair fetal development, leading to congenital disease and other pregnancy complications. In this Review, we discuss the mechanisms of pathogen recognition in the maternal and fetal compartments of the placenta and the consequences of these responses to pregnancy outcomes.

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Fig. 1: Structure of human and mouse placenta.
Fig. 2: Pathogen sensing and innate immune responses at the maternal–fetal interface.

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Acknowledgements

The authors acknowledge US National Institutes of Health grant R01AI145828 for support.

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M.S.D. is a consultant or on a Scientific Advisory Board for Inbios, IntegerBio, Akagera Medicines, GlaxoSmithKline, Merck and Moderna. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions, Bavarian Nordic and Moderna.

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Glossary

Decidualization

The functional and morphological transformation that occurs within the endometrium. Decidualization encompasses endocrine, biochemical and immunological changes to form the decidual lining that allows blastocyst implantation. It involves the recruitment of leukocytes and the differentiation of endometrial fibroblasts into terminally differentiated decidual stromal cells. Decidualization includes the repression of genes involved in inflammation and the induction of genes that promote cellular proliferation and angiogenesis, immune tolerance and tissue invasion.

Epiblast

(Also known as the primitive ectoderm). One of the two cell layers derived from the inner cell mass of the blastocyst. During gastrulation, the epiblast differentiates into the three primary germ layers (ectoderm, mesoderm and endoderm). The other layer of the inner cell mass of the epiblast, the hypoblast, gives rise to the yolk sac, which in turn contributes to the generation of the chorion.

Interferon-λ

(IFNλ; also referred as type III interferon or IL28/29). A multi-gene family of antiviral cytokines (IFNL1, IFNL2, IFNL3, IFNL4) that share similar responses with type I interferons (for example, IFNα/β). Both type I and type III interferons are produced in response to pathogen-associated molecular pattern (PAMP)-generated microbial infections and activation of pattern-recognition receptors (PRRs). Paracrine or autocrine engagement of the heterodimeric IFNλ receptor (IL28Rα/IL10Rβ) by IFNλ results in activation of JAK/STAT signalling pathways, nuclear translocation of STAT1 and STAT2, and transcriptional induction of hundreds of interferon-stimulated genes (ISGs). Because of cell type and tissue-limited restriction of the IL28Rα subunit, antiviral responses by IFNλ are elicited preferentially at barrier surfaces, including the skin, the respiratory and intestinal tracts, and the maternal–fetal interface. In contrast to type I interferons, IFNλ responses are less inflammatory, but in some cases often more sustained, suggesting complementary actions of these two set of cytokines in the response to viral infections at tissue barrier sites.

‘M2-like’ macrophages

‘M1’ and ‘M2’ are terms used to define macrophages activated in vitro as pro-inflammatory (when exposed to interferon-γ (IFNγ) or lipopolysaccharide (LPS)) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10). In vivo macrophages are highly specialized, transcriptomically dynamic and heterogeneous, and the M1 or M2 classification is too simplistic to explain their functional status. However, these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory, respectively.

Oropouche virus

Orthobunyavirus oropoucheense is an arthropod-transmitted tripartite, negative-sense RNA virus in the Peribunyaviridae family. Infection in humans causes Oropouche fever in Latin America and the Caribbean, a mild and self-limited febrile illness that wanes after a week. However, some individuals progress to haemorrhagic manifestations or neurological sequelae from encephalitis, which can cause considerable morbidity. Recently, vertical transmission of Oropouche virus was reported, as infection in women was linked temporally to miscarriages, fetal microcephaly and congenital anomalies.

Pyroptosis

A type of inflammatory cell death triggered by the formation of pores in the cell membrane by gasdermin protein family members. This cell death occurs after activation of the inflammasome, which is triggered by infection or other insults to the cell. Pore formation at the cell membrane facilitates the release of inflammatory cytokines such as IL-1β and IL-18 into the extracellular space, which act as danger signals (damage-associated molecular patterns (DAMPs)) for adjacent cells, further amplifying the inflammatory response.

Teratogenic

Refers to a molecule, microorganism or agent that can cause congenital abnormalities in the context of exposure to the fetus during pregnancy. The relative deleterious effects of a teratogen depend on the agent, dose, duration and gestational stage at which the exposure occurs. Common teratogenic agents include infectious agents (viruses, bacteria, parasites), physical agents (radiation), chemicals (mercury, herbicides), prescription or recreational drugs and ingested alcohol.

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Alippe, Y., Hatterschide, J., Coyne, C.B. et al. Innate immune responses to pathogens at the maternal–fetal interface. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01191-0

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