The central finding is therefore contextual rather than universal: galectins regulate cellular processes that support maternal-fetal tolerance, tissue remodeling and antiviral defense, so the same regulatory activity may have different consequences during infection. Pregnancy requires the maternal immune system to tolerate fetal tissue carrying paternal antigens while retaining the ability to control pathogens. The placenta is central to this balancing act.

Its fetal component consists of chorionic villi, whereas the maternal component is the decidua, where coordinated immune populations support tolerance, spiral-artery remodeling and pregnancy maintenance. During the first trimester, the interface has a relatively homogeneous cellular and functional immune landscape. Decidual natural killer cells are the predominant decidual leukocytes, accounting for approximately 70% of the total, followed by dendritic cells, decidual macrophages and regulatory T cells.

Physical barriers formed by placental cells, together with immunoglobulins, chemokines and cytokines, add further protection. This environment must support fetal development without eliminating antimicrobial responses. Galectins are endogenous, non-glycosylated lectins that recognize carbohydrates, particularly β-galactoside-rich structures distributed among placental cell types.

They are classified as prototype, tandem-repeat or chimera-type proteins, with galectin-3 belonging to the chimera group. Their carbohydrate-recognition domain contains two antiparallel beta-sheets arranged as a beta-sandwich, and the architecture of this domain contributes to differences in ligand specificity. Unlike most secreted proteins, galectins lack a conventional signal peptide and are exported through unconventional pathways that bypass the endoplasmic reticulum and Golgi apparatus.

The molecular details of that export remain incompletely understood in most tissues. Once released, galectins can occur as soluble molecules or within extracellular vesicles and engage cell-surface and extracellular-matrix ligands. Their distribution across the placenta is distinct.

Galectin-1 is broadly expressed in the decidua, endometrium, extravillous trophoblast and syncytiotrophoblast, as well as in decidual natural killer and regulatory T cells. Galectin-3 is concentrated in cytotrophoblasts, villous trophoblast and endometrium. Galectin-9 occurs mainly in cytotrophoblasts, decidua and endometrium, whereas galectin-13, also called placental protein 13, is almost exclusively expressed by syncytiotrophoblast.

Galectins bind a broad set of partners, including integrins, receptor tyrosine kinases, Notch-signaling components, neuropilin-1, cell-adhesion molecules, immune receptors and the glycosphingolipid GM1. Their cellular partners support trophoblast adhesion, migration, invasion, angiogenesis, vascular adaptation and immune regulation, linking carbohydrate recognition to both placental development and maternal-fetal tolerance. Specific glycan context also shapes galectin activity.

Sialic acid can mask N-acetyllactosamine epitopes and thereby alter galectin-glycan interactions, while the type of sialic-acid linkage can influence galectin-1 binding. First-trimester trophoblasts release highly sialylated antigens that contribute to immune regulation, and impaired trophoblast sialylation has been associated with embryonic developmental failure and maternal complement activation. Redox conditions can also alter galectin structure through disulfide-bond formation, while glycan binding can protect against oxidative inactivation.

These biochemical observations show that galectin behavior is influenced by molecular environment, but they do not establish how such changes affect infection in the maternal-fetal interface. Systemic studies provide some of the clearest evidence that galectins can restrain damaging inflammation during cytomegalovirus infection. In a mouse model of CMV-induced hepatitis, galectin-3-deficient mice had increased viral replication, more severe inflammation and enhanced TNF-α-mediated cell death, whereas recombinant galectin-3 reduced liver injury.

In another murine model, galectin-9-deficient mice infected with murine CMV showed exaggerated natural killer-cell activation and inflammatory responses. These findings support protective regulatory roles for galectin-3 and galectin-9 in the tested mouse systems. They do not, however, demonstrate that the same mechanisms operate in infected human placentas.

Decidual natural killer cells differ functionally from peripheral natural killer cells, leaving the relevance of galectin-9 interactions with TIM-3 at the maternal-fetal interface unresolved. Direct placental evidence for CMV is more limited. CMV has tropism for trophoblast cells and can replicate efficiently in cytotrophoblasts.

Infection may produce placental edema and fibrosis, impair oxygen and nutrient transport to the fetus and contribute to fetal growth restriction. A proteomic analysis of amniotic fluid from pregnancies involving fetuses with congenital CMV found elevated galectin-3-binding protein, an immunomodulatory glycoprotein that interacts directly with galectin-3. Higher concentrations were associated with severe congenital CMV, but the association does not establish causation, transmission or a mechanism linking galectin-3 activity to placental injury.

The review identifies this as an important gap: it remains unclear whether altered galectin pathways contribute to disease severity, respond to infection or both. Zika virus illustrates how apparently conflicting observations can arise at different biological scales. In a study of 45 placentas from women infected with Zika virus, placentas associated with congenital Zika syndrome showed villous edema, coagulative necrosis and trophoblast detachment.

Galectin-3 was markedly overexpressed in cytotrophoblasts and colocalized with the viral NS2B antigen. The same study found Hofbauer-cell hyperplasia and increased proliferation of Hofbauer cells and trophoblasts. In contrast, transcriptomic analysis using trophoblasts derived from discordant twins with congenital Zika syndrome showed significant downregulation of LGALS3 following infection.

Tissue-level overexpression and cell-intrinsic downregulation may represent different aspects of the response, but the observations do not establish whether galectin-3 is protective or whether its increase is a consequence of infection-associated remodeling. Zika evidence outside the placenta further cautions against labeling galectins uniformly antiviral. Galectin-1 on human neural progenitor cells can cooperate with AXL as part of a viral-entry complex: antibody-mediated blockade and LGALS1 silencing reduced infection, and galectin-1-deficient mice had lower Zika viral loads and fewer virus-induced pathological changes.

During pregnancy, Zika virus is thought to reach the placenta primarily through the decidua. It can infect decidual cells, cytotrophoblasts and extravillous trophoblasts, while syncytiotrophoblasts remain largely resistant. Interferon signaling and other antiviral pathways are activated after infection, but direct functional evidence connecting galectins to these responses at the maternal-fetal interface remains scarce.

Findings from neural cells and mice therefore cannot be treated as proof of a placental effect. HIV studies provide substantial evidence of virus-promoting activity, including mechanisms that may be relevant to persistence and mother-to-child transmission. Galectin-1 can bridge the HIV-1 envelope glycoprotein gp120 to the CD4 receptor, increasing viral attachment, and can promote reactivation of latent reservoirs through NF-κB signaling.

Galectin-3 has been associated with cell-to-cell viral dissemination and replication, although it can also promote death of infected macrophages. Galectin-9 has a dual role involving viral transcription, inflammation and host immune responses; increased expression has been associated with enhanced HIV transcription in CD4-positive T cells during antiretroviral therapy and with reactivation of latent reservoirs. Elevated galectin-3-binding protein in breast milk has been associated with higher maternal viral load and increased risk of postnatal transmission, while higher serum galectin-9 has been correlated with poorer cognitive performance in adolescents with vertically acquired HIV.

These are clinical associations, not demonstrations that the galectins cause transmission or neurological outcomes. The review calls for experiments that can distinguish whether altered galectin expression is a consequence of infection or a contributor to viral entry, replication, persistence, inflammation and placental-cell responses. The authors specifically propose combining single-cell and spatial methods with placental organoids, decidual immune-cell systems and functional infection models.

Such studies could define the functions of individual galectins in specific placental populations and determine whether galectin-13 participates in congenital infection, a question that remains largely unanswered. The emerging picture is neither a simple shield nor an obvious gateway. Galectins are context-dependent regulators whose net effect can depend on where and when they act, and their roles within infected human placentas still require direct functional testing before stronger conclusions can be drawn.

Subject of Research: Context-dependent roles of placental galectins in antiviral immunity and congenital viral infection

Article Title: Galectins at the maternal-fetal interface: shield or gateway to infections?

Article References: Mattos, G. D., Pereira, N. Z., & Sato, M. N. (2026). Galectins at the maternal-fetal interface: shield or gateway to infections?. Frontiers in Cellular and Infection Microbiology, 16, Article 1960770. https://doi.org/10.3389/fcimb.2026.1960770

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1960770

Keywords: galectins, placenta, maternal-fetal interface, viral infection, cytomegalovirus, Zika virus, HIV, immune tolerance, congenital infection, placental immunity, maternal-fetal, interface