In May 2015, an outbreak of Zika virus began in Brazil and in the subsequent year spread to other parts of South and Central America and the Caribbean. While the risk for North Americans was generally restricted to travelers to these regions and has since moderated, this outbreak has served as an indication (along with the current SARS-CoV-2 pandemic) that emerging infectious diseases will continue to pose risk to human populations. Zika is a flavivirus that shares characteristics with West Nile, dengue, and yellow fever viruses but has unique pathophysiology: most individuals, including pregnant women, infected with Zika virus are asymptomatic, however the effect of Zika virus on developing fetuses can be devastating. When a pregnant woman is infected, the virus can spread to her child through the same blood flow in the placenta that supplies the fetus with nutrients and oxygen. In the fetal brain, Zika virus can cause abnormalities in development including cerebral calcifications, atrophy, and other neurological insults, most dramatically, microcephaly, potentially linked to certain strains of the virus.
Even if the fetus is not directly impacted, maternal infection is associated with adverse pregnancy outcomes including miscarriage, fetal growth restriction and still birth. Equally troubling is that infants that may appear relatively normal at birth can later exhibit developmental abnormalities, even if there is no evidence that the infant is infected at birth.
We have demonstrated that pregnancy loss is a reproducible characteristic of infection of pregnant rhesus monkeys, and early gestation fetuses are particularly vulnerable to maternal infection. We hypothesize that adverse pregnancy outcomes in early gestation are more complicated than simply vertical transmission and viral pathogenic effect on the fetus.
We have focused on three major projects with maternal infection Zika virus in pregnant rhesus monkeys. First, we are working with virologist and pediatrician collaborators to determine the impact of maternal infection on the postnatal infant outcome maternal infection and its association with infection at the maternal-fetal interface. Second, we are working to identify the impact of maternal Zika infection on the maternal immune environment directly at the maternal-fetal interface, using high-dimensional flow cytometric approaches, and use histologically approaches to localize the pathway that Zika takes across the placenta and fetal membranes. Third, we have demonstrated Zika infection of trophoblast (placental) stem cells and their differentiated derivatives and documented subsequent alterations in placental cell gene transcription and secreted extracellular vesicles. We will further explore the impact of maternal stressors on placental extracellular vesicles in vivo to determine whether they can be used as a readout of placental infection, vertical virus transmission, and the risk of fetal infection.
These studies will establish a tool set applicable to a broad range of pathogens that attack the reproductive tract and the maternal-fetal interface, often causing reproductive failure, fetal loss and neonatal death.
Ultrasound images of third trimester Rhesus fetus. Data captured includes head and bone measurements including the presence of of any abnormalities (e.g., brain or placental calcification).