SARS-CoV-2 Transplacental Transmission: A Rare Occurrence? An Overview of the Protective Role of the Placenta.

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic, caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global public health crisis, causing substantial concern especially to the pregnant population. Pregnant women infected with SARS-CoV-2 are at greater risk of devastating pregnancy complications such as premature delivery and stillbirth. Irrespective of the emerging reported cases of neonatal COVID-19, reassuringly, confirmatory evidence of vertical transmission is still lacking. The protective role of the placenta in limiting in utero spread of virus to the developing fetus is intriguing. The short- and long-term impact of maternal COVID-19 infection in the newborn remains an unresolved question. In this review, we explore the recent evidence of SARS-CoV-2 vertical transmission, cell-entry pathways, placental responses towards SARS-CoV-2 infection, and its potential effects on the offspring. We further discuss how the placenta serves as a defensive front against SARS-CoV-2 by exerting various cellular and molecular defense pathways. A better understanding of the placental barrier, immune defense, and modulation strategies involved in restricting transplacental transmission may provide valuable insights for future development of antiviral and immunomodulatory therapies to improve pregnancy outcomes.

Cell-type specific distribution and activation of type I IFN pathway molecules at the placental maternal-fetal interface in response to COVID-19 infection.

Background and objective: COVID-19 infection in pregnancy significantly increases risks of adverse pregnancy outcomes. However, little is known how the innate immunity at the placental maternal-fetal interface responds to COVID-19 infection. Type I IFN cytokines are recognized as a key component of the innate immune response against viral infection. In this study, we specifically evaluated expression of IFN antiviral signaling molecules in placentas from women infected with COVID-19 during pregnancy. Methods: Expression of IFN activation signaling pathway molecules, including cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), interferon regulatory factor 3 (IRF3), Toll-like receptor 7 (TLR7), mitochondrial antiviral-signaling protein (MAVS), and IFNß were determined in formalin-fixed paraffin embedded (FFPE) placental tissue sections (villous and fetal membrane) by immunostaining. A total of 20 placentas were examined, 12 from COVID-19 patients and 8 from non-COVID-19 controls. Patient demographics, clinical data, and placental pathology report were acquired via EPIC medical record review. Results: Except BMI and placental weight, there was no statistical difference between COVID and non-COVID groups in maternal age, gestational age at delivery, gravity/parity, delivery mode, and newborn gender and weight. In COVID-exposed group, the main pathological characteristics in the placental disc are maternal and fetal vascular malperfusion and chronic inflammation. Compared to non-COVID controls, expression of IFN activation pathway molecules were all upregulated with distinct cell-type specific distribution in COVID-exposed placentas: STING in villous and decidual stromal cells; IRF3 in cytotrophoblasts (CTs) and extra-villous trophoblasts (EVTs); and TLR7 and MAVS in syncytiotrophoblasts (STs), CTs, and EVTs. Upregulation of STING, MAVS and TLR7 was also seen in fetal endothelial cells. Conclusions: STING, IRF3, TLR7, and MAVS are key viral sensing molecules that regulate type I IFN production. Type I IFNs are potent antiviral cytokines to impair and eradicate viral replication in infected cells. The finding of cell-type specific distribution and activation of these innate antiviral molecules at the placental maternal-fetal interface provide plausible evidence that type I IFN pathway molecules may play critical roles against SARS-CoV-2 infection in the placenta. Our findings also suggest that placental maternal-fetal interface has a well-defined antiviral defense system to protect the developing fetus from SARS-CoV-2 infection.

[Effects of Toxoplasma gondii infection on mouse and human uterine natural killer cells].

OBJECTIVE: To examine the effects of Toxoplasma gondii infection on the proportion, quantity, differentiation and function of mouse and human uterine natural killer cells (uNK cells), so as to explore the role of uNK cells in abortion of early pregnancy caused by T. gondii infection. METHODS: Pregnant mice were injected intraperitoneally with T. gondii tachyzoites on day 6.5 of pregnancy, and the abortion mouse model caused by T. gondii infections was constructed. Mouse uterine lymphocytes were isolated on day 9.5 of pregnancy. Human uterine lymphocytes were isolated from fresh human decidual specimens after abortion in normal early pregnancy and co-cultured with tachyzoites of the T. gondii RH strain for 48 h at T. gondii/uterine lymphocytes ratios of 0.5:1, 1:1 and 2:1. The phenotypes of mouse uNK cells (CD122, NK1.1, DX5) and human uNK cells (CD3, CD56, CD11b, CD27) and the expression of intracellular cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were detected by flow cytometry. Mouse and human uNK cells were sorted by magnetic beads, and the cytotoxicity of uNK cells was tested using the lactate dehydrogenase (LDH) release assay at effector/target cell ratios of 1:1, 5:1, 10:1 and 20:1 with mouse or human uNK cells as effector cells and mouse YAC-1 cells or human K562 cells as target cells. RESULTS: On day 9.5 of pregnancy, the mouse abortion rate was significantly higher in the infected group than that in the control group (83.02% vs. 3.51%; χ2 = 71.359, P < 0.001). Significantly lower absolute number of uNK cells [(4 547 ± 1 610) cells/mouse vs. (8 978 ± 3 339) cells/mouse; U = 2.000, P < 0.05], lower NK1.1 expression on uNK cell surface [(74.53 ± 8.37)% vs. (93.00 ± 1.11)%; U = 0.000, P < 0.05], higher proportion of NK1.1-DX5-cells [(20.10 ± 8.03)% vs. (5.04 ± 0.68)%; U = 0.000, P < 0.05], lower proportion of NK1.1+ DX5+ cells [(21.70 ± 12.48)% vs. (45.75 ± 2.26)%; U = 0.000, P < 0.05] and higher IFN-γ expression [(16.74 ± 1.36)% vs. (8.13 ± 1.90)%; U = 0.000, P < 0.05] were detected in the infected group than in the control group, while no significant difference was seen in TNF-α expression between the two groups [(67.98 ± 9.20)% vs. (52.93 ± 10.42)%; U = 2.000, P > 0.05]. The mouse uNK cells showed a strong cytotoxicity in the infected group, and the cytotoxicity gradually increased with the effector/target cell ratio. The cytotoxicity of uNK cells against YAC-1 cells was 2.30%, 4.32%, 8.12% and 12.65% in the infected group and 1.21%, 1.63%, 2.51% and 3.22% in the control group at effector/target cell ratios of 1:1, 5:1, 10:1 and 20:1, respectively. Following co-culture of human uterine lymphocytes and tachyzoites of the T. gondii RH strain for 48 h, the proportion [TOX 2:1 group vs. control group: (6.61 ± 1.75)% vs. (17.48 ± 4.81)%; F = 7.307, P < 0.01], and absolute number of human uNK cells in uterine lymphocytes of human uNK cells in uterine lymphocytes [TOX 2:1 group vs. control group: (12 104 ± 5 726) cells/well vs. (65 285 ± 21 810) cells/well; H = 11.540, P < 0.01] were significantly lower in the infected group than in the control group. A lower proportion of CD56brightCD16- NK cells [TOX 2:1 group vs. control group: (25.25 ± 5.90)% vs. (36.03 ± 4.51)%; F = 3.213, P > 0.05] and higher proportion of CD56dimCD16+ NK cells [TOX 2:1 group vs. control group: (11.15 ± 2.15)% vs. (7.09 ± 2.24)%; F = 2.992, P > 0.05] were detected in uNK cells in the infected group than in the control group, and the ratio of CD56brightCD16- cells/CD56dimCD16+ cells was significantly lower in the infected group than in the control group [TOX2:1 group vs. control group: (2.37 ± 0.92) vs. (5.58 ± 2.39); H = 8.228, P < 0.05]. In addition, the proportion of CD11b+CD27- cells in human uNK cells was significantly higher in the infected group than in the control group [TOX 2:1 group vs. control group: (30.28 ± 6.91)% vs. (17.48 ± 4.67)%; H = 6.556, P < 0.05], while no significant differences were found between the two groups in terms of IFN-γ [TOX 2:1 group vs. control group: (14.13 ± 1.28)% vs. (15.19 ± 1.64)%; F = 1.639, P > 0.05] or TNF-α expression [TOX 2:1 group vs. control group: (54.76 ± 10.02)% vs. (50.33 ± 3.67)%; F = 0.415, P > 0.05]. Human uNK cells presented a strong cytotoxicity in the infected group, and the cytotoxicity gradually increased with the effector/target cell ratio. The cytotoxicity of human uNK cells against K562 cells was 11.90%, 28.11%, 49.91% and 73.35% in the infected group and 12.21%, 21.63%, 33.51% and 48.22% in the control group at effector/target cell ratios of 1:1, 5:1, 10:1 and 20:1, respectively. CONCLUSIONS: T. gondii infection presents diverse effects on the differentiation and secretion ability of mouse and human uNK cells. However, T. gondii infection causes a reduction in the absolute number and enhances the cytotoxicity of both mouse and human uNK cells.

SARS-CoV-2 Infection in Pregnant Women: Neuroimmune-Endocrine Changes at the Maternal-Fetal Interface.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has devastating effects on the population worldwide. Given this scenario, the extent of the impact of the disease on more vulnerable individuals, such as pregnant women, is of great concern. Although pregnancy may be a risk factor in respiratory virus infections, there are no considerable differences regarding COVID-19 severity observed between pregnant and nonpregnant women. In these circumstances, an emergent concern is the possibility of neurodevelopmental and neuropsychiatric harm for the offspring of infected mothers. Currently, there is no stronger evidence indicating vertical transmission of SARS-CoV-2; however, the exacerbated inflammatory response observed in the disease could lead to several impairments in the offspring's brain. Furthermore, in the face of historical knowledge on possible long-term consequences for the progeny's brain after infection by viruses, we must consider that this might be another deleterious facet of COVID-19. In light of neuroimmune interactions at the maternal-fetal interface, we review here the possible harmful outcomes to the offspring brains of mothers infected by SARS-CoV-2.

Why are pregnant women susceptible to COVID-19? An immunological viewpoint.

The 2019 novel coronavirus disease (COVID-19) was first detected in December 2019 and became epidemic in Wuhan, Hubei Province, China. COVID-19 has been rapidly spreading out in China and all over the world. The virus causing COVID-19, SARS-CoV-2 has been known to be genetically similar to severe acute respiratory syndrome coronavirus (SARS-CoV) but distinct from it. Clinical manifestation of COVID-19 can be characterized by mild upper respiratory tract infection, lower respiratory tract infection involving non-life threatening pneumonia, and life-threatening pneumonia with acute respiratory distress syndrome. It affects all age groups, including newborns, to the elders. Particularly, pregnant women may be more susceptible to COVID-19 since pregnant women, in general, are vulnerable to respiratory infection. In pregnant women with COVID-19, there is no evidence for vertical transmission of the virus, but an increased prevalence of preterm deliveries has been noticed. The COVID-19 may alter immune responses at the maternal-fetal interface, and affect the well-being of mothers and infants. In this review, we focused on the reason why pregnant women are more susceptible to COVID-19 and the potential maternal and fetal complications from an immunological viewpoint.