Trends in Microbiology
Insights into viral transmission at the uterine–placental interface
Section snippets
Intrauterine infections associated with pregnancy complications
Fewer than 50% of all pregnancies in healthy women survive beyond early gestation [1]. Many failures are due to chromosomal abnormalities; the etiology of others is unknown. Certain viruses and pathogenic bacteria are associated with mid to late pregnancy complications, but little is known about infection early in gestation when the placenta undergoes transformations that are crucial for fetal survival. Recent studies on biopsy specimens from the maternal–fetal interface infected with human
Development of the human placenta
The human placenta is composed of villi that float in maternal blood and also villi within the uterine wall that anchor the placenta and attach the fetus to the mother. The individual chorionic villus contains a connective core that contains fetal blood vessels and numerous macrophages (Hofbauer cells) that often lie under a thick basement membrane (see Figure I in Box 1; Zone I). Placentation is a stepwise process whereby cytotrophoblast progenitor cells, attached to the basement membrane as a
Invasive cytotrophoblasts express novel differentiation molecules
During placentation, cytotrophoblasts switch from an epithelial type to a mesenchymal type: a precisely regulated process [8]. Cytotrophoblasts express novel adhesion molecules and proteinases that enable the cells' attachment and invasion, as well as immune-modulating factors that play a role in maternal tolerance of the hemiallogeneic fetus (Box 1) [9]. Interstitial invasion requires downregulation of integrins characteristic of epithelial cells and expression of novel integrins that promote
Intrauterine viral infection
Intrauterine viral infections can ascend from the genital tract or spread via the hematogenous route (Table 1). Circumstantial evidence for ascending CMV infection includes high rates of bacterial vaginosis (i.e. pathogenic bacteria) and infection of the cervical epithelium [16]. Patterns of placental infection in utero suggest hematogenous spread from the infected uterus [17]. CMV, a ubiquitous virus secreted in bodily fluids, causes asymptomatic infections in healthy individuals and is
Patterns of CMV infection at the uterine–placental interface
CMV infection is the major viral cause of well-documented birth defects [18] (Figure 2). Symptoms range in severity depending on primary or reactivated maternal infection during, or shortly before, gestation 26, 27. Examination of biopsy specimens from early-gestation placentas revealed that intrauterine CMV infections could spread to the placenta [17]. As illustrated by immunohistological staining, when the decidua and placenta were actively infected in utero, viral replication proteins were
CMV infection downregulates cytotrophoblast differentiation molecules and impairs invasion
Congenital CMV infection is associated with intrauterine growth restriction (Figure 2), a placental defect related to impaired remodeling of uterine arteries by invasive cytotrophoblasts, compromising blood flow to the placenta [11]. CMV productively infects isolated placental cytotrophoblasts in vitro 2, 29, 30, 31. Infected cytotrophoblasts alter differentiation, as evidenced by dysregulated expression of stage-specific immune and adhesion molecules and MMP-9 2, 32. At late stages of
Animal models for congenital CMV infection
Because CMV is species-specific, the main obstacle to developing animal models is the difference in placental architecture, which precludes virus transmission across the placenta and congenital infection. The exceptions are endogenous CMV infections in humans, rhesus macaques and guinea pigs [3]. Some placental types do not directly contact maternal blood, and those that do have multiple cell layers separating the maternal and fetal circulations (e.g. murine placenta). Maternal–fetal transfer
Concluding remarks
Villus explants and differentiating cytotrophoblasts infected in vitro offer models to study human CMV and viruses that infect the placenta and the fetus. However, many questions remain unanswered (Box 3). Understanding basic molecular pathogenic mechanisms is the crucial first step in the rational design of treatments that address the causes, rather than the consequences, of intrauterine infection. Conceivably, there are several points at which intervention is possible. Women could be
Acknowledgements
We are grateful to our colleagues Susan Fisher, Olga Genbacev, Yan Zhou and Virginia Winn for thoughtful discussions, James Nachtwey and Hsin-Ti Chang for technical assistance, Keith Jones for preparation of the graphic illustrations, and Mary McKenney for editing the manuscript. Work done in the author's laboratory was supported by Public Health Service grants AI46657, AI53782 and EY13683 from the National Institutes of Health and grants from the March of Dimes Birth Defects Foundation and the
Glossary
- Anchoring villi:
- Composed of cytotrophoblasts that aggregate and form cell columns that invade the uterine wall and endothelium. Connected to the basal plate and attach the fetus to the uterus. Stabilize the position of the villus tree in the maternal bloodstream.
- Basal plate:
- The basal portion of the maternal–fetal junctional zone that adheres to the delivered placenta. Composed of invasive cytotrophoblasts, endometrial stromal cells, decidual cells, uterine-placental vessels and endometrial
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2020, Antiviral ResearchCitation Excerpt :For in utero placenta infection, viral particles have been detected in epithelia of decidua endothelial glands but also in floating villi. This type of infection in placenta-specific tissues can cause lesions during pregnancy through virus-induced apoptosis or edema (Pereira et al., 2005; Weisblum et al., 2011). Since 2010, the World Health Organization (WHO) recommends the use of either artesunate (ART) or quinine to treat severe malaria in pregnancy from the first trimester (National Center for Biotechnology, 2015; McGready et al., 2012; Roussel et al., 2017).