Human trophoblast stem cells restrict human cytomegalovirus replication

Area of Science:

• Reproductive biology
• Virology
• Stem cell biology

Background:

• Congenital human cytomegalovirus (HCMV) infection, a leading cause of fetal growth restriction and pregnancy loss, originates from placental infection.
• Understanding HCMV's impact on placental development is hindered by species specificity and limitations of primary trophoblast models.
• Human trophoblast stem cells (TSCs) offer a novel model for studying early placental development and viral interactions.

Purpose of the Study:

• To assess the utility of human trophoblast stem cells (TSCs) as a model for HCMV infection in the first-trimester placenta.
• To investigate how HCMV interacts with TSCs and their differentiated progeny (extravillous trophoblasts and syncytiotrophoblasts).
• To elucidate the mechanisms by which HCMV infection may compromise placental function and development.

Main Methods:

• Human trophoblast stem cells (TSCs) were infected with HCMV.
• Immunofluorescence assays and flow cytometry were used to detect viral gene expression.
• RNA sequencing was performed to analyze viral and host gene expression patterns.
• Antiviral responses and signaling pathways (e.g., Wnt/β-catenin) were assessed in infected cells.

Main Results:

• HCMV productively infected TSCs, extravillous trophoblasts (EVTs), and syncytiotrophoblasts (STBs).
• Infected TSCs primarily expressed immediate early viral genes, with atypical viral gene expression kinetics compared to fibroblasts.
• Canonical antiviral responses were largely absent; instead, infection dysregulated genes involved in cell identity, differentiation, and Wnt signaling.
• HCMV infection perturbed trophoblast differentiation pathways without productive replication.

Conclusions:

• Human trophoblast stem cells (TSCs) serve as a valuable model for studying HCMV infection in the early placenta.
• HCMV establishes non-productive infections in TSCs and differentiated trophoblasts, evading typical antiviral responses.
• Disruption of trophoblast differentiation and cell fate pathways by HCMV infection represents a potential mechanism for placental dysfunction and adverse pregnancy outcomes.