Biology subjects

Diveley, E.

Publications and source records attributed to Diveley, E..

3 recordsLinked to original sources

bioRxiv2026

Trophoblast ferroptosis restricts SARS-CoV-2 spread in the placenta

Prenatal SARS-CoV-2 infection is associated with adverse pregnancy outcomes, but placental mechanisms that restrict viral spread remain unclear. Here we show that SARS-CoV-2 exposure induces ferroptosis-linked iron dysregulation in the placenta as a host defense. Human placentas from early gestation SARS-CoV-2-exposed pregnancies exhibited persistent viral protein expression at term, iron accumulation, disrupted localization of iron transport proteins, and reduced expression of the ferroptosis inhibitor, GPX4. In trophoblast cells and newly generated stem cell-derived trophoblast organoids (SC-TOs) with physiological apical-out polarity, infection with live SARS-CoV-2 Delta variant suppressed expression of iron efflux transporter, ferroportin and ferroptosis inhibitors, GPX4 and PLA2G6, promoting lipid peroxidation and ferroptotic signaling. Sub-lethal pharmacological activation of ferroptosis reduced viral titers in trophoblasts, indicating an antiviral function. Together, these results uncover a new mechanism through which the placenta attempts to restrict SARS-CoV-2 replication. However, this protective response is accompanied by placental iron sequestration, which may compromise maternal-fetal iron transfer and help explain iron deficiency and anemia reported in infants born after prenatal SARS-CoV-2 exposure, highlighting a delicate balance between iron and ferroptosis-mediated protection and damage with implications for pregnancy outcomes.

cell biology↗

bioRxiv2025

SARS-CoV-2 infection disrupts syncytial and endothelial integrity and alters PLGF levels in the placenta

IntroductionSARS-CoV-2 infection during pregnancy has been associated with an increased risk for several pregnancy-related disorders, particularly preeclampsia (PE). However, there are limited studies determining the impact of SARS-CoV-2 on placental physiology and function. MethodsPlacental samples were acquired from two large prospective cohorts: STOP-COVID19 and REBRACO studies. Placental villous tissues (VTs) were collected from pregnant women who tested positive for SARS-CoV-2 without PE during pregnancy. Immunohistochemistry and immunofluorescence were used to assess pathological features known to be altered in PE, including 1) syncytial knot formation; 2) alterations in renin-angiotensin system components; 3) and endothelial integrity. Maternal serum was collected to examine AT1 autoantibodies levels using an immunoassay. ResultsSARS-CoV-2 viral proteins spike, nucleocapsid, and ORF3a were observed in the syncytiotrophoblast layer and stroma of placental VT. SARS-CoV-2-infected placentas exhibited increased numbers of syncytial knots, which were positive for Flt-1 and SARS-CoV-2 viral proteins. In addition, the presence of placental infarctions and excessive fibrin deposits was also observed in infected placentas. Infection was associated with decreased placental expression of PlGF and an increase in the placental Flt-1/PlGF expression ratio, mostly driven by PlGF. No significant changes in maternal serum AT1AA levels were observed. Finally, SARS-CoV-2-infected placentas exhibited a significant decrease in vimentin expression. DiscussionSARS-CoV-2 infection negatively impacts placental integrity in the form of increased syncytial knots, dysregulated RAS components, and endothelial damage. Since all these features are similarly disrupted in PE, this could be a mechanism through which SARS-CoV-2 infection during pregnancy increases the risk of a PE-like syndrome.

microbiology↗

bioRxiv2024

SARS-CoV-2 ORF3a Protein Impairs Syncytiotrophoblast Maturation, Alters ZO-1 Localization, and Shifts Autophagic Pathways in Trophoblast Cells and 3D Organoids

SARS-CoV-2 infection poses a significant risk to placental physiology, but its impact on placental homeostasis is not well understood. We and others have previously shown that SARS-CoV-2 can colonize maternal and fetal placental cells, yet the specific mechanisms remain unclear. In this study, we investigate ORF3a, a key accessory protein of SARS-CoV-2 that exhibits continuous mutations. Our findings reveal that ORF3a is present in placental tissue from pregnant women infected with SARS-CoV-2 and disrupts autophagic flux in placental cell lines and 3D stem-cell-derived trophoblast organoids (SC-TOs), impairing syncytiotrophoblast differentiation and trophoblast invasion. This disruption leads to protein aggregation in cytotrophoblasts (CTB) and activates secretory autophagy, increasing CD63+ extracellular vesicle secretion, along with ORF3a itself. ORF3a also compromises CTB barrier integrity by disrupting tight junctions via interaction with ZO-1, mediated by its PDZ-binding motif, SVPL. Colocalization of ORF3a and ZO-1 in SARS-CoV-2-infected human placental tissue supports our in vitro findings. Deleting the PDZ binding motif in the ORF3a protein (ORF3a-noPBM mutant) restored proper ZO-1 localization at the cell junctions in an autophagy-independent manner. Lastly, we demonstrate that constitutive ORF3a expression induces SC-TOs to transition towards a secretory autophagy pathway likely via the PBM motif, as the ORF3a-NoPBM mutants showed a significant lack of CD63 expression. This study demonstrates the functional impact of ORF3a on placental autophagy and reveals a new mechanism for the activation of secretory autophagy, which may lead to increased extracellular vesicle secretion. These findings provide a foundation for exploring therapeutic approaches targeting ORF3a, specifically focusing on its PBM region to block its interactions with host cellular proteins and limiting placental impact.

microbiology↗