Editorial: Infectious diseases in maternal-fetal interface: role of immune system to combat this pathology and avoid or minimize a possible vertical transmission

The human maternal-fetal interface, represented primarily by the placenta, constitutes the main barrier between the maternal and fetal compartments during pregnancy. It consists of a maternal component, the decidua, and a fetal component formed by cells that give rise to the chorionic villi (1). The placenta originates from the trophoblast surrounding the blastocyst and, following implantation, these cells differentiate into villous and extravillous cytotrophoblasts (2). Villous cytotrophoblasts give rise to the syncytiotrophoblast, which covers the placental villi, acts as a barrier against pathogens, and participates in maternal-fetal exchange (3, 4). Extravillous cytotrophoblasts, in turn, contribute to spiral artery remodeling and establish a tolerogenic environment through interactions with decidual immune cells (5–7). Together with the basal lamina, mesenchyme, and fetal blood vessels, these structures form the placental barrier (4).

The integrity of this barrier is essential to protect the fetus from pathogens (4, 8, 9). However, some pathogens, such as protozoa and viruses, can cross the placental barrier and impair fetal development (10). This challenge is further complicated by the maternal immune system’s need to adapt throughout pregnancy. During the first trimester, a Th1 response characterized by IL-8, IFN-γ and TNF-α contributes to implantation, vascular remodeling and uterine repair, but its persistence may promote pregnancy loss (11, 12). During the second trimester, a Th2 response predominates, characterized by IL-4, TGF-β1 and IL-10, supporting fetal development and maternal tolerance to the allogeneic fetus. Toward the end of pregnancy, the Th1 response becomes predominant again, contributing to preparation for labor (13–15). An imbalance between these responses may contribute to complications such as preeclampsia (16, 17), whereas a Th2-skewed environment may increase susceptibility to infections and facilitate vertical transmission (9, 18). Thus, infections at the maternal-fetal interface represent a unique immunological challenge, requiring a balance between pathogen control and the immune tolerance necessary to sustain pregnancy.

The primary objective of this Research Topic was to bring together studies addressing the interactions among pathogens, the placenta and the immune system, with emphasis on the mechanisms underlying placental invasion, immune responses and vertical transmission, as well as diagnostic, therapeutic and preventive strategies. Eight articles were published, including original research studies, reviews and a brief research report, addressing different aspects of infections during pregnancy and their consequences.

Mbianda et al. investigated γδ T-cell differentiation in placental malaria and demonstrated compartment-specific differentiation, with an increased TEMRA phenotype associated with IL-8 and IL-33, as well as enhanced mitochondrial metabolic activity. These findings suggest that cytokines and metabolic reprogramming modulate γδ T-cell function and may represent potential therapeutic targets.

Mizobuchi et al. evaluated the effects of maternal Leishmania donovani infection on offspring immune responses. Although the offspring did not develop persistent infection or acquired immune memory, they showed sex-specific immunopathological alterations: males had increased erythrophagocytosis and anemia, whereas females had increased parasitism and hepatic inflammation. These findings demonstrate that maternal infection can induce long-lasting alterations in offspring immunity.

Choi et al. investigated a vaccine strategy against different strains of congenital cytomegalovirus (cCMV). The combination of antibodies targeting glycoprotein B (gB) and a T-cell response against IE1 antigen reduced CMV transmission to undetectable levels, whereas the gB-only vaccine provided limited protection. These results highlight the potential of combining humoral and cellular immune responses to achieve cross-strain protection against cCMV.

Jiménez-Escutia et al. evaluated how gestational diabetes-associated hyperglycemia affects the placental response to Streptococcus agalactiae (GBS). The combination of hyperglycemia and infection increased bacterial proliferation and disrupted the syncytial barrier, while reducing TLR-2 and inflammatory mediators such as TNF-α, MCP-1, and MIP-1β, thereby impairing the recruitment of monocytes and NK cells. These findings suggest that hyperglycemia promotes bacterial persistence and loss of placental barrier integrity.

Kahraman and Celina reviewed 38 cases of Crimean-Congo hemorrhagic fever during pregnancy, reporting maternal survival of 68% and fetal or neonatal survival of only 39%. The interaction between pregnancy’s Th2-predominant immune environment and endothelial and hepatic alterations may promote viral replication, hemorrhage, and coagulopathy, while also mimicking conditions such as HELLP syndrome and severe preeclampsia. The authors emphasize the need for early diagnosis, virological confirmation, and safe antiviral therapies.

SARS-CoV-2 also represents an important threat during pregnancy and has been associated with adverse outcomes, including maternal mortality, preterm birth, and stillbirth (19), with the virus also detected in the placenta and fetus (20, 21). In this context, Packer et al. demonstrated that vaccination was associated with a lower incidence of severe maternal disease, despite higher levels of some cytokines, including TNF-α, suggesting immune priming. They observed no specific fetal inflammatory response, supporting a role for vaccination in modulating the maternal immune response.

Yuan et al. evaluated the neutralizing antibody response to the SARS-CoV-2 NB.1 variant in domestic cats. NB.1 exhibited greater immune escape than JN.1, with a 2.9-fold reduction in neutralizing antibody titers, although none of the animals tested showed evidence of infection. Although the study did not directly investigate the maternal-fetal interface, it contributes to understanding immune escape and variant surveillance, both of which are relevant to developing vaccination strategies.

Finally, Chikungunya virus (CHIKV) can cause significant morbidity in congenitally infected children (22), and viral antigens have been detected in different placental cell types, accompanied by alterations in immune cells and cytokines (23). In this context, Zeng et al. reviewed the mechanisms underlying chronic chikungunya-associated arthritis, proposing a cascade involving viral persistence, myeloid cell metabolic dysregulation, Treg/Th17 imbalance, and autoimmune-like tissue injury. Although not focused on congenital infection, this study expands our understanding of viral persistence and immunometabolic dysregulation during arboviral infections, highlighting potential intervention targets in maternal infection.

Collectively, the eight articles highlight the complexity of the interactions among pathogens, metabolism, immune responses, and the placental barrier. These studies reinforce that understanding the mechanisms governing pathogen persistence, control, and transmission is essential for developing more effective diagnostic, preventive, and therapeutic strategies, ultimately contributing to reducing the impact of congenital infections on maternal and fetal health.

Editorial on the Research Topic Infectious diseases in maternal-fetal interface: role of immune system to combat this pathology and avoid or minimize a possible vertical transmission

Author contributions

BB: Writing – original draft, Writing – review & editing. LS: Writing – original draft, Writing – review & editing. UK: Writing – original draft, Writing – review & editing.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

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