Abstract The placenta is the interface between the fetal and maternal environments during mammalian gestation, critically safeguarding the health of the developing fetus and the mother. Placental trophoblasts origin from embryonic trophectoderm that differentiates into various trophoblastic subtypes through villous and extravillous pathways. The trophoblasts actively interact with multiple decidual cells and immune cells at the maternal–fetal interface and thus construct fundamental functional units, which are responsible for blood perfusion, maternal–fetal material exchange, placental endocrine, immune tolerance, and adequate defense barrier against pathogen infection. Various pregnant complications are tightly associated with the defects in placental development and function maintenance. In this review, we summarize the current views and our recent progress on the mechanisms underlying the formation of placental functional units, the interactions among trophoblasts and various uterine cells, as well as the placental barrier against pathogen infections during pregnancy. The involvement of placental dysregulation in adverse pregnancy outcomes is discussed. Summary Sentence We summarize recent progresses on the regulatory mechanisms involved in the formation of placental functional units, including maternal–fetal material exchange, blood perfusion, endocrine, immune adaptation, and defense barrier against infection.

The mystery of the life tree: the placentas

Herpes simplex virus type 2 (HSV-2) infection affects 24 million births annually and is associated with adverse pregnancy outcomes, including neonatal herpes; however, the mechanisms underlying in utero transmission of HSV-2 are largely unknown. We examined the effects of primary HSV-2 infection during early pregnancy on gestational outcomes in a novel, clinically relevant mouse model. Pregnant C57BL/6 mice were infected intravaginally with 102–105 pfu/mL HSV-2 on gestation day (gd) 4.5. Controls were infected, nonpregnant, diestrus-staged mice and pregnant, uninfected mice. Compared to nonpregnant mice, pregnant mice were 100-fold more susceptible to HSV-2 infection. Three days post-inoculation (gd7.5), viral DNA was present in implantation sites, but pregnancy outcomes were largely unaffected by infection. Eight days post-inoculation (gd12.5), HSV-2 DNA persisted in placental tissues, resulting in inflammation and hemorrhage. Fetal and placental weights were reduced and fetal loss was observed with high viral doses. HSV-2 DNA and increased expression of pro-inflammatory mediators were detected in fetal tissues at gd12.5, signifying viral transmission and fetal infection, even with low viral doses. This mouse model shows a dose-dependent effect of primary HSV-2 infection on pregnancy outcomes and suggests that fetal loss may occur due to placental inflammation, thus providing valuable insight into in utero transmission of HSV-2.

Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model.

Recent reports have suggested a tight relationship between viral infections and neurodevelopmental disorders. In this regard, fetal brain damage can be caused by direct viral infection or induced immune responses and cytokine storm. Although recent years have seen phenomenal progress in diagnosing autism spectrum disorders (ASD) and identifying genetic and epigenetic causative factors contributing to this group of neurodevelopmental disorders, almost 60% cases in children remain of unknown etiology. Little is known about the collective pathophysiology of ASD. In this regard, epidemiological data suggest that viral infections during pregnancy are associated with high risk of having an autistic child. Although SARS-CoV-2 infections have been documented in pregnant women, we do not yet know whether COVID-19 pandemic will contribute to the onset of autism-like features in the offspring or impact autistic individuals. We hypothesize that ASD are programmed in the mother's womb and that uterine, not peripheral, immune activation is the initial trigger to induce fetal brain developmental anomalies. We further hypothesize that exposure to infections only during a temporal window of pregnancy impact the onset of ASD-like pathology, particularly in the male fetus/offspring. We will discuss the role of uterine regulatory T cells and their inflammatory trans-differentiation in the pathophysiology of ASD and comment on possible therapeutic intervention options.

Viral Infections and Temporal Programming of Autism Spectrum Disorders in the Mother's Womb

Objective: This study estimated CMV molecular prevalence in placental biopsies as well as in umbilical blood cord and its correlation with infection of pregnant women and their newborns to determinate vertical transmission risks. Design: A cross-sectional study Setting: Obstetric Center of the University Hospital in Rio Grande, Brazil Population: 496 pregnant women and their newborns Methods : Biopsies were collected from peripheral and central portions of each placenta, separated on fetal and maternal interfaces, matched with cord blood, totaling 1488 samples. PCR technique and sequencing were used to investigate the prevalence. Main Outcome Measures: Bivariate and multivariate analysis were performed to determinate sociodemographic, clinical and gynecological data associated to CMV vertical transmission. Results: CMV DNA was found in 5.2% of placental maternal interface and 5.4% of fetal interface with a positive result for CMV in 3.6% in cord blood. In more than 90% of the cases, there was no match between positive CMV DNA cord blood and positive placentas, indicating vertical transmission ascending from genital tract. The income factor (less than 1 minimum wage) was significantly associated with prevalence of CMV in placentas (p = 0.03). In cord blood samples, non-white skin color and early age at the onset of sexual intercourse were risk factors associated with the infection (p = 0.04). Conclusions: The occurrence of CMV DNA found in cord blood suggests the pattern observed appears to be ascending from genital tract of asymptomatic mothers. Economical and environmental factors present a negative impact on fetal-maternal transmission of cytomegalovirus. 

https://www.authorea.com/doi/pdf/10.22541/au.167388304.47717537

Risk factors associated with vertical transmission of CMV in Southern Brazil: a cross-sectional study based on the molecular prevalence of the virus in placental tissue and umbilical blood cord

Preeclampsia is one of the most common disorders that poses threat to both mothers and neonates and a major contributor to perinatal morbidity and mortality worldwide. Viral infection during pregnancy is not typically considered to cause preeclampsia; however, syndromic nature of preeclampsia etiology and the immunomodulatory effects of viral infections suggest that microbes could trigger a subset of preeclampsia. Notably, SARS-CoV-2 infection is associated with an increased risk of preeclampsia. Herein, we review the potential role of viral infections in this great obstetrical syndrome. According to in vitro and in vivo experimental studies, viral infections can cause preeclampsia by introducing poor placentation, syncytiotrophoblast stress, and/or maternal systemic inflammation, which are all known to play a critical role in the development of preeclampsia. Moreover, clinical and experimental investigations have suggested a link between several viruses and the onset of preeclampsia via multiple pathways. However, the results of experimental and clinical research are not always consistent. Therefore, future studies should investigate the causal link between viral infections and preeclampsia to elucidate the mechanism behind this relationship and the etiology of preeclampsia itself.

Implication of viruses in the etiology of preeclampsia.

Cytomegalovirus (CMV) is one of the most common intrauterine infection virus, which can cause intrauterine transmission through the placenta, resulting in abortion, stillbirth and congenital malformations. In this study, the co-culture extravillous trophoblast (EVT) HTR8/SVneo cell model of CMV infection was established in vitro. The toxicity of CMV infected EVT was determined, and then, the cell invasion experiment was conducted to evaluate the effect on the invasion ability of EVT cell lines. Western blot and real-time PCR were used to detect the related cytokines in the PI3K/AKT signalling pathway in cells. Flow cytometry was used to detect the immune function related factors of the supernatant of CMV culture on decidual NK cells. The TCID50 of CMV virus was 10-5.4 . The results of immunofluorescence showed that a large number of fluorescent green of CMV pp65 antigen signals appeared in the cytoplasm of CMV infection group. CMV could infect and replicate EVT cells and inhibited cell proliferation. The expression of proteins PDK1, AKT-S473 and AKT-S308 was significantly increased in CMV infection group. The levels of IL-17, IL-4 and IFN-γ were 8.7 ± 0.48%, 12.17 ± 0.61% and 6.66 ± 0.25%, respectively, in CMV infection group. The above results indicated that CMV infection inhibited EVT cells proliferation, weakened the invasion ability and inhibited the immune function of NK cells at the maternal-fetal interface, resulting in the abnormal maternal-fetal crosstalk.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.15638

Effects of cytomegalovirus infection on extravillous trophoblast cells invasion and immune function of NK cells at the maternal-fetal interface.

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Effects of cytomegalovirus infection on extravillous trophoblast cells invasion and immune function of NK cells at the maternal-fetal interface.