Mouse models show how Zika migrates into the placenta

In two mouse models of Zika, the virus was observed migrating from the bloodstream into the placenta, where it multiplied, then spread into the foetal circulation and infected the brains of the developing pups.

The models, developed by a team of researchers at Washington University School of Medicine in St. Louis, provide a basis to develop vaccines and treatments, and to study the biology of Zika virus infection in pregnancy.

“This is the first demonstration in an animal model of in utero transmission of Zika virus, and it shows some of the same outcomes we’ve been seeing in women and infants,” said Michael Diamond, MD, PhD, a professor of medicine, molecular microbiology and pathology and immunology. “This could be used in vaccine trials, to find out whether vaccinating the mother can protect against uterine infection. You also could test therapeutics, once the mother got infected, to see if they could arrest the transmission to the foetus or prevent damage to the foetus.”

Since mice with normal immune systems are able to fight off Zika infection, Diamond and colleagues weakened the mice’s immune systems before infecting them with the virus.

In one model, the researchers genetically modified mice to lack a molecule called interferon alpha receptor that plays a key role in the immune response to viral infections. In the other model, they injected mice with antibodies against the molecule.

The scientists infected pregnant mice with Zika virus about a week after conception and examined their placentas and foetuses six to nine days later. Both mouse models reflected some of the key aspects of human Zika infection. In the mice, as in humans, the virus crossed from the mother’s bloodstream into the foetus’s and infected the developing brain, where damage to neurons was observed.

Microcephaly – which is marked by abnormally small heads, the most striking result of human infection – was not observed in either model. This may be due to differences in how mouse and human brains develop.

“Unlike in humans, a significant amount of neurodevelopment in mice actually occurs after birth, especially in the cerebral cortex, which is the part of the brain damaged in microcephaly,” Diamond said.

Zika virus concentration higher in the placenta

Indira Mysorekar, PhD, and postdoctoral fellow Bin Cao, PhD, found the virus in the placenta at 1,000 times the concentration in the maternal blood, suggesting that it had not just migrated to the placenta, but multiplied there.

In the genetically-modified mice, Zika infection caused the death of most of the foetuses, and the remaining foetuses were much smaller than normal. The placentas showed damage: they were shrunken, with a reduced number of blood vessels. Such placentas would be unable to supply enough oxygen and nutrients to a developing foetus, a condition known as placental insufficiency, which causes abnormally slow foetal growth and, in severe cases, foetal death.

Placental insufficiency, abnormally small foetuses and miscarriages have been reported in pregnant women infected with Zika virus, as well.

In both models, the virus also was detected in the foetal brain. The researchers observed cell death in the brains of infected foetuses, but there were no obvious abnormalities in the overall structure of the brain.

In the model in which mice were injected with antibodies, the effect of Zika infection was less severe. The foetuses survived, although some were smaller than normal. Diamond and colleagues plan to use this model to study whether prenatal Zika virus infection causes long-term neurological problems in pups born without obvious brain damage.

Not all babies born to women infected with Zika during pregnancy develop microcephaly; some seem healthy at birth. But it is unknown whether such babies will face developmental or intellectual challenges as they grow up.

Diamond and Mysorekar, an associate professor of obstetrics and gynecology, and of pathology and immunology, also want to identify the molecules the virus latches onto to get into and through the placenta, so they can block them.