Biology subjects

McColl, E.

Publications and source records attributed to McColl, E..

4 recordsLinked to original sources

bioRxiv2026

Human placental trophoblasts support sustained Treponema pallidum replication and reveal new candidate host pathways implicated in congenital syphilis

Congenital syphilis is a leading cause of preventable stillbirth, yet the mechanisms that enable Treponema pallidum subsp. pallidum, the etiological agent of syphilis, to traverse and persist within the human placenta are virtually unknown. This knowledge gap reflects, in part, the fastidious nature of T. pallidum, which has historically only been propagated in rabbit epithelial cells. Here, we demonstrate that T. pallidum replicates and can be propagated long-term in human placental trophoblast models. We identified three human trophoblast cell lines, JEG-3, BeWo, and HTR-8, that sustained robust T. pallidum replication for over 55 days. Confocal imaging with GFP-expressing T. pallidum demonstrated bacterial adherence to trophoblast cultures. To identify human placental pathways that may support T. pallidum replication and persistence, we performed bulk transcriptomic profiling of the three trophoblast lines co-cultured with T. pallidum for 3 or 7 days. Our findings revealed conserved host responses involving increased cholesterol synthesis, suppressed type I interferon signaling, and disrupted extracellular matrix organization. These data implicate host metabolic rewiring, innate immune attenuation, and extracellular matrix remodeling as candidate pathways that may promote T. pallidum invasion, replication and persistence within the placenta. Together, these models represent the first human placental systems capable of supporting efficient, long-term T. pallidum growth and provide a foundation for mechanistic studies of congenital syphilis pathogenesis.

microbiology↗

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↗

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↗

bioRxiv2024

Placentas from SARS-CoV-2 infection during pregnancy exhibit foci of oxidative stress and DNA damage

ProblemCOVID-19 during pregnancy is linked to increased maternal morbidity and a higher incidence of preterm births, yet the underlying mechanisms remain unclear. Cellular senescence, characterized by the irreversible cessation of cell division, is a critical process in placental function and its dysregulation has been implicated in pregnancy complications like preterm birth. Senescence can be induced by various stressors, including oxidative stress, DNA damage, and viral infections. Method of StudyIn this study, we determined whether COVID-19 had an impact on placental senescence. We examined placentas from women infected with SARS-CoV-2 (n=10 term, 4 preterm) compared to uninfected controls (n=10 term, 3 preterm). The placentas were analyzed for SARS-CoV-2 infection/replication (Spike and Nucleocapsid viral proteins), markers of DNA damage ({gamma}H2AX) and oxidative stress (ROS), and senescence (telomere length; cell cycle regulators, SASP). ResultsWhile no overall differences in cellular senescence markers were observed between the COVID-19 positive and negative groups, we found increased secreted SASP markers and confocal microscopy revealed localized areas of oxidative stress and DNA damage in the placentas from COVID-19 positive cases. ConclusionsThese findings indicate that SARS-CoV-2 infection induces localized placental damage, warranting further investigation into its impact on maternal and perinatal outcomes.

microbiology↗