Infections at the maternal-fetal interface: an overview of pathogenesis and defence

Abstract

Infections are a major threat to human reproductive health, and infections in pregnancy can cause prematurity or stillbirth, or can be vertically transmitted to the fetus leading to congenital infection and severe disease. The acronym 'TORCH' (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus) refers to pathogens directly associated with the development of congenital disease and includes diverse bacteria, viruses and parasites. The placenta restricts vertical transmission during pregnancy and has evolved robust mechanisms of microbial defence. However, microorganisms that cause congenital disease have likely evolved diverse mechanisms to bypass these defences. In this Review, we discuss how TORCH pathogens access the intra-amniotic space and overcome the placental defences that protect against microbial vertical transmission.

Fig. 1. Routes of transmission across the placenta and consequences of infection.

a | TORCH (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus) pathogens can access the intra-amniotic compartment through multiple mechanisms, including direct transplacental transmission, placental damage or disruption and/or fetal–maternal haemorrhage. In addition, pathogens can be transmitted by ascending the genital tract. b | Infections in pregnancy can affect the maternal host, fetus and/or the placenta itself. The results of infection and the inflammatory response have consequences at each site.

Fig. 2. Structure and cellular composition of the maternal–fetal interface.

a | The structure of the maternal–fetal interface includes the maternal decidua and the fetus-derived placenta. The maternal uterine microvasculature is remodelled to form spiral arteries, which deliver blood to chorionic villi in the intervillous space. b | The placenta undergoes a series of rapid morphological changes throughout gestation. In early pregnancy (left), the blastocyst differentiates into the embryo and the trophectoderm, the earliest cell type that will form the placenta. The invasive trophoblasts begin to invade the decidua, where the early syncytiotrophoblast forms and infiltrates into the endometrium. Throughout the first trimester (middle), chorionic villi form and remain immature until the later stages of this trimester. Immature villi are covered in the syncytiotrophoblast layer, with a contiguous layer of cytotrophoblasts lying below this layer. The stroma of the villi in the first trimester contains fetal vessels, which begin to form at ~6–8 weeks of gestation. The maternal microvasculature undergoes extensive remodelling during the first trimester, with the placenta transitioning to haemochorial at the end of this stage of gestation. In the second and third trimesters (right), chorionic villi mature and remain covered by the syncytiotrophoblast. However, unlike the immature villi of the first trimester, the cytotrophoblast layer becomes discontinuous in the later stages of gestation. At this stage, the fetal microvasculature is fully developed, and the villous stroma becomes enriched in fetus-derived Hofbauer cells, which reduce in number closer to full-term.

Fig. 3. Placental defences against pathogens.

Given its role as a primary barrier to the haematogenous spread of infectious agents, the human placenta has evolved disparate and non-overlapping mechanisms of antimicrobial defence. These can be separated into at least three categories, physical defences (left), the constitutive release of antimicrobial effectors (middle) and/or robust innate immune response to infection (right). Physical defences include the lack of cell–cell junctions of the syncytiotrophoblast layer, preventing inflammation-mediated damage of intercellular junctions that could compromise the integrity of this barrier. Additional physical defences include the dense cortical actin network lying sub-apical to the dense brush border of the syncytiotrophoblast. Another form of defence involves the constitutive release of potent antimicrobial effectors such as antiviral microRNAs in extracellular vesicles, cytokines (for example, type III interferons), and antimicrobial peptides (middle). The placenta also responds to pathogens with potent innate immune signalling, which further enhances the release of antimicrobial defence substances (right).

Fig. 4. Possible mechanisms of vertical transmission.

The mechanisms by which many TORCH (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus) pathogens access the fetus are unclear. However, studies suggest that some of these pathogens may use similar pathways to bypass the placental barrier. These mechanisms include infection of extravillous trophoblasts (EVTs; green cells) and/or infection of the maternally derived decidua, such as through direct infection of maternal immune cell populations. Other possible routes include direct infection of transmission across chorionic villi, through direct infection of the syncytium (SYN) or through inflammation-mediated damage of the syncytiotrophoblast layer that disrupts the barrier and allows transmission.

Fig. 5. Placental malaria in endemic areas.

Schematic of the maternal–fetal interface in an uninfected state (left panel). Schematic of the maternal–fetal interface in the setting of malaria (right panel). The parasite (yellow) accesses the placenta through the maternal circulation. The intervillous space then becomes a site of parasite replication where the parasite undergoes surface antigenic variation, ultimately leading to immune escape and further replication causing maternal anaemia. Maternal anaemia and parasitaemia substantially prevent nutrient transport across the placenta, which can lead to nutrient deprivation for the developing fetus.