Parks, W. T. | Search bioRxiv

bioRxiv2024

Placental Network Differences Among Obstetric Syndromes Identified With An Integrated Multiomics Approach

The placenta is essential for a healthy pregnancy, and placental pathology can endanger both maternal and fetal health. Placental function is affected by dynamic, complex, and interconnected molecular, cellular, and environmental events; therefore, we need a systems biology approach to study disease in normal physiological placenta function. We use placental multiomics (short and bulk transcriptomics, untargeted metabolomics, and targeted proteomics) paired with clinical data and placental histopathology reports from 321 placentas across multiple obstetric conditions: fetal growth restriction (FGR), FGR with pregnancy-related hypertension (FGR+HDP), preeclampsia (PE), and spontaneous preterm delivery (PTD). We first performed cellular deconvolution to estimate cell type numbers from bulk transcriptomes: FGR+HDP placentas were the most different from control placentas driven by a higher estimated number of extravillous trophoblast (p<0.0001). Next, we evaluated the impact of fetal sex and gestational age on analyte levels, adjusting for these confounders. We then generated obstetric condition-specific correlation networks and identified communities of related analytes associated with physiology and disease. We demonstrated how network connectivity and its disruption in disease can be used to identify signatures unique to a clinical outcome. We examined a community defined in control placentas for which the most connected node was miR-365a-3p in contrast to the corresponding community in FGR+HDP placentas for which the most connected node was hypoxia-induced miR-210-3p. From this community, we identified a signature containing mRNA transcripts implicated in placental dysfunction (e.g. FLT1, FSTL3, HTRA4, LEP, and PHYHIP). This signature distinguishes between FGR+HDP placentas and placentas of differing clinical outcomes in high-dimensional space. These findings illustrate the power of systems biology-driven interomics network analysis in a single tissue type, laying the groundwork for future multi-tissue studies.

systems biology↗

bioRxiv2022

HAPPY: A deep learning pipeline for mapping cell-to-tissue graphs across placenta histology whole slide images

Accurate placenta pathology assessment is essential for managing maternal and newborn health, but the placentas heterogeneity and temporal variability pose challenges for histology analysis. To address this issue, we developed the Histology Analysis Pipeline.PY (HAPPY), a deep learning hierarchical method for quantifying the variability of cells and micro-anatomical tissue structures across placenta histology whole slide images. HAPPY differs from patch-based features or segmentation approaches by following an interpretable biological hierarchy, representing cells and cellular communities within tissues at a single-cell resolution across whole slide images. We present a set of quantitative metrics from healthy term placentas as a baseline for future assessments of placenta health and we show how these metrics deviate in placentas with clinically significant placental infarction. HAPPYs cell and tissue predictions closely replicate those from independent clinical experts and placental biology literature.

bioinformatics↗

bioRxiv2018

ZIKA VIRUS INFECTION AT MID-GESTATION RESULTS IN FETAL CEREBRAL CORTICAL INJURY AND FETAL DEATH IN THE OLIVE BABOON.

Zika virus (ZIKV) infection during pregnancy in humans is associated with an increased incidence of congenital anomalies including microcephaly as well as fetal death and miscarriage and collectively has been referred to a Congenital Zika Syndrome (CZS). Animal models for ZIKV infection in pregnancy have been developed including mice and macaques. While microcephaly has been achieved in mice via direct injection of ZIKV into the fetal brain or via interference with interferon signaling, in macaques the primary fetal CZS outcome are ocular defects. In the present study we develope the olive baboon (Papio anubis), as a model for the vertical transfer of ZIKV during pregnancy. We infected four mid-gestation, timed-pregnant baboons with the French Polynesian ZIKV isolate (104 ffu) and examined the acute phase of vertical transfer by stopping the study of one dam at 7 days post infection (dpi), two at 14 dpi and one at 21 dpi. All dams exhibited mild to moderate rash and conjunctivitis; three of four dams exhibited viremia at 7 dpi. Of the three dams studied to 14 to 21 days, only one still exhibited viremia on day 14. Vertical transfer of ZIKV to the fetus was found in two pregnancies; in one, vertical transfer was associated with fetal death at [~]14 dpi. In the other, vertical transfer was observed at 21 dpi. Both fetuses had ZIKV RNA in the fetal cerebral cortex as well as other tissues. The 21 dpi fetal cerebral cortex exhibited notable defects in radial glia, radial glial fibers, loss and or damage of immature oligodendrocytes and a loss in neuroprogenitor cells (NPCs). In addition, indices of pronounced neuroinflammation were observed including astrogliosis, increased microglia and IL-6 expression. The dams studied to 14 dpi (n=2) and 21 dpi (n=1) exhibited a anti-ZIKV IgM response and IgG response (21 dpi) that included transfer of the IgG to the fetal compartment (cord blood). The severity of systemic inflammatory response (cytokines and chemokines) reflected the vertical transfer of ZIKV in the two pregnancies. As such, these events likely represent the early mechanisms that lead to microcephaly and/or other CNS pathologies in a primate infected with ZIKV and are the first to be described in a non-human primate during the acute phase of ZIKV infection with a contemporaneous ZIKV strain. The baboon thus represents a major NHP for advancing as a model for ZIKV induced brain pathologies to contrast and compare to humans as well as other NHPs such as macaques.\n\nAUTHOR SUMMARYZika virus is endemic in the Americas, primarily spread through mosquitos and sexual contact. Zika virus infection during pregnancy in women is associated with a variety of fetal pathologies now referred to as Congenital Zika Syndrome (CZS), with the most severe pathology being fetal microcephaly. Developing model organisms that faithfully recreate Zika infection in humans is critical for future development of treatments and preventions. In our present study, we infected Olive baboons at mid-gestation with Zika virus and studied the acute period of viremia and transfer of Zika virus to the fetus during the first three weeks after infection to better understand the timing and mechanisms leading to CZS. We observed Zika virus transfer to fetuses resulting in fetal death in one pregnancy and in a second pregnancy, significant damage to the frontal cortex of the fetal brain consistent with development of microcephaly, closely resembling infection in pregnant women. Our baboon model differs from macaque non-human primate models where the primary fetal outcome during pregnancy following infection with contemporary strains of Zika virus is ocular pathology. Thus, the baboon provides a promising new non-human primate model to further compare and contrast the consequences of Zika virus infection in pregnancy to humans and macaques to better understand the disease.

neuroscience↗