The Immunological Role of the Placenta in SARS-CoV-2 Infection-Viral Transmission, Immune Regulation, and Lactoferrin Activity

Abstract

A pandemic of acute respiratory infections, due to a new type of coronavirus, can cause Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) and has created the need for a better understanding of the clinical, epidemiological, and pathological features of COVID-19, especially in high-risk groups, such as pregnant women. Viral infections in pregnant women may have a much more severe course, and result in an increase in the rate of complications, including spontaneous abortion, stillbirth, and premature birth-which may cause long-term consequences in the offspring. In this review, we focus on the mother-fetal-placenta interface and its role in the potential transmission of SARS-CoV-2, including expression of viral receptors and proteases, placental pathology, and the presence of the virus in neonatal tissues and fluids. This review summarizes the current knowledge on the anti-viral activity of lactoferrin during viral infection in pregnant women, analyzes its role in the pathogenicity of pandemic virus particles, and describes the potential evidence for placental blocking/limiting of the transmission of the virus.

Keywords: COVID-19; lactoferrin; mother’s placenta; oxidative stress; pregnant women.

Figure 3

Lactoferrin effects on SARS-CoV-2 docking to cell surface receptors (CSR): Sialoside glycan (SIA) and heparan sulfate (HS). (A) SARS-CoV-2 attachment and entry to host cell. SIA and HS chains present on membrane glycoproteins (PGs) facilitate the attachment of the virion to the cell surface. Then the resulting complex binding to the cellular receptor (ACE2), initiating the process of internalization. (B) Human lactoferrin was found to exhibit anti-viral activity against SARS-CoV-2 infection, likely mechanisms of action are: Interaction with one of the proteins in the virion envelope S, M, or E, or competition for binding to glycan chains and/or probable the ACE2 receptor [162,175].

Figure 1

Implications of SARS-CoV-2 virus infection at the maternal–fetal interface. The placental function disruption (histomorphological alterations) as a consequence of maternal clinical implications of COVID-19 (e.g., hypoxia, cytokine storm) and/or placenta infection, as well as probable fetal infection (vertical transmission) may result in pregnancy complications, compromise fetal health and long term adverse neonatal outcomes.

Figure 2

The defense mechanism of the placenta and potential infection sites of SARS-CoV-2. Placental properties that prevent SARS-CoV-2 infection include: Physical blockade, release/synthesis of anti-viral molecules (miRNA, IFN III, NF-κB), and stimulation of immune defense by decidual and fetal immune cells. The SARS-CoV-2 fetal infection may occur due to placental barrier breakage or via ascending route. Abbreviations: ACE2, Angiotensin converting enzyme 2; EVTs, extravillous trophoblasts; IFN, interferon; miRNA, microRNA; MSC, mesenchymal stromal cells; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NK cell, natural killer cell; STB, syncytiotrophoblast; T reg cell, regulatory T cell.

Figure 4

The lactofferin-mediated immune response of anti-viral cells [175]. Main activities and cites of action of lactoferrin (LF) in host defense against viral entry. The diagram illustrates the main effects of lactoferrin on T and B cells, macrophages, and dendritic cells (DC). In the initial stage of a specific immune response, antigen-presenting cells activate naïve T cells, presenting them with antigens and providing additional costimulatory signals. Activated T lymphocytes undergo intensive division and form functionally differentiated subpopulations: Effector T lymphocytes and memory T lymphocytes. Effector T lymphocytes migrate to the site of infection, where they inactivate the pathogens present there, and then die by apoptosis. B-cells capture foreign antigens and presents them to T-cells. Activated B-cells (after antigen binding) transform into antibody secreted plasma cells or memory B-cells. Lactoferrin modulates antigen-presenting cell action, including migration and activation, inactivates cells infected with the virus, activates B cells that destroy infected cells with the participation of T cells. Moreover, LF affects the expression of soluble immune mediators (cytokines, chemokines, and other effector molecules) to regulate inflammatory and immune responses.