The placenta is essential organ with various physiological, immune, and endocrine functions needed—to nourish and protect the fetus. It is composed of cells from two different individuals—mother and fetus
[68]. The fetal part of the placenta forms from the chorionic sac—including the amnion, yolk sac, chorion, and allantois. The outer layer of the placenta is called the trophoblast and consists of two layers: The cytotrophoblast layer (inner) and the syncytiotrophoblast layer (outer). The maternal part comes from the endometrium and is called the decidua with maternal vessels
[69]. Between these two regions is located the intervillous space filled with maternal blood
[70]. The basic functional units of the placenta are fetus-derived chorionic villi (CV) with fetoplacental vessels. CV are formed and maintained by the fusion of: syncytiotrophoblast (STB), extravillous trophoblasts (EVTs), and cytotrophoblasts (CTBs)
[68]. The placenta’s unique structure and function determine the protective properties against most pathogens
[71]. Its role in infections is multi-directional and involves: (1) Physical blockade of viral entry; (2) active anti-viral function and in case of infection (3) immunomodulatory action (). The most important elements of the placenta as a physical barrier are: (i) A dense network of branch microvilli and periodical regeneration of the most outer STB layer
[72], the lack of intracellular gap junctions between STB cells
[73]; (ii) dense actin cytoskeletal network, forming a brush border at the apical surface of the STB layer
[74]; (iii) limited expression of TLR or internalization receptors as E-Cadherin at the STB layer
[75]; (iv) little to no expression of caveolins at STB surface
[76]; (v) the basement membrane beneath the villous cytotrophoblast
[77]. The immunological role of the placenta in infections depends on may things, including its immunomodulatory property with trophoblast-immune crosstalk. It has been suggested as a crucial component of the innate immune response. Immune cells from the fetal and maternal compartments interact to provide an intricate balance between fetal tolerance (pregnancy maintenance) and anti-microbial defense in case of infection. Moreover, the breakage or breach of the decidual or syncytial barrier continuity initiates a strong innate immune reaction against pathogens. The maternal decidua is composed of stromal cells and leukocytes (40% of decidua)
[78]. 50–70% of decidual leukocytes are NK cells, 20–30% are macrophages, 10–30% are T cells, including regulatory T cells (Treg), and approximately 2% are DC’s
[79][80][81]. The proportion of immune cells vary throughout pregnancy, with an increase in the proportion of T cells at term
[82]. During the first trimester of pregnancy, macrophages and NK cells accumulate around the trophoblastic cells
[83][84]. The fetal part of the placenta—the chorionic villi contains, at the core part, fetal macrophages (Hofbauer cells), fetal endothelial cells, fibroblasts, and mesenchymal stem/stromal cells (MSCs)
[85][86][87]. The trophoblast releases several immunomodulatory molecules, such as a secretory leukocyte protease inhibitor (SLPI), β-defensins, and expresses “maternal lactoferrin”
[88]. During pregnancy, TLRs (TLR-3, TLR-7, TLR-8, and TLR-9) are expressed on the surface of trophoblast, decidua, Hofbauer cells, endothelial cells, and chorioamniotic membranes. Furthermore, a soluble form of TLR2 is also present in amniotic fluid
[88]. The expression of TLRs by trophoblast varies through the gestation (first trimester: villous cytotrophoblasts (vCTBs) and EVTs; term: STB and EVTs)
[89]. Its immunoregulatory function includes caspase activation, cytokine production, and inflammatory response induction, as well as the release of anti-microbial peptides and proteins into the amniotic fluid
[90]. They also play an important role in bridging innate and adaptive systems
[91]. Acquired viral infections may disturb the immune regulation at the border of the mother and the fetus, leading to fetal damage, even when the virus does not reach it directly
[92]. The TLR-3 receptor in the first trimester of pregnancy may mediate a rapid anti-viral response
[93][94], and induce the production of cytokines, type I and III IFN
[95]. Similarly, TLR7 induces the synthesis of anti-viral cytokines and play a role in preventing intrauterine transmission of some viruses (e.g., HBV)
[96]. Cytokines and interferons are important mediators in healthy pregnancies, due to their role in regulating cell function, proliferation, and gene expression. However, their deregulation may disrupt the developmental paths of the fetus and placenta
[97]. Lactoferrin may also play a similar role to TLR and interferon receptors. Moreover, to ensure the maternal humoral protection of fetus and neonates, the maternal antibodies are actively transported to the fetus via the neonatal IgG receptor expressed on the STB surface
[98].