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November 25, 2020 09:00pm
By Sara Karlovitch, Assistant Editor
Pregnant mouse models injected with the Zika virus saw an increase in miscarriages and babies born with thin brain tissue.
The Zika virus may cause miscarriages or cause babies to be born with thin brain tissue and inflammation in brain cells.
In astudypublished inNatureCommunications, investigators injected the Zika virus directly into the reproductive tract of pregnant mouse models with complete immune systems.
The results of the study showed that the virus could cross the placenta and infect the fetus by creating disorganization in the cellular layers of that placenta. Furthermore, the investigators found a mechanism that Zika may use to prevent antiviral proteins in the body from protecting cells from the virus.
“We need to find a way to stop transmission of Zika through the placenta into the fetus, because that is where the damage is being done,” said co-leader Sabra L. Klein, PhD. “In the placentas of our mice, we’re seeing a defense against Zika being mounted, but falling short, especially in early pregnancy, a time that corresponds to the first trimester in humans.”
The investigators hope that the findings will lead to the development of treatment or vaccine targets to help fight the virus.
“If we can determine what is happening, we may be able to find ways to minimize or even eliminate what can be devastating consequences for children of infected mothers,” said co-leader Irina Burd, MD, PhD.
The investigators developed a novel mouse model to help understand the mechanisms behind Zika transmission to the fetus. The mice differed from other models in that they had completely intact immune systems closer in similarity to humans, to allow the investigators to examine the mechanisms in mounting an immune response.
For the study, the virus was injected into the reproductive tract of the pregnant mice during the equivalent of the first trimester in a human. Because different animal species may clear infections in different ways, the investigators wanted to ensure that the virus was getting to the most relevant tissues of the mice.
Several different strains of the Zika virus were used for the study, including older strains from the 1968 outbreak in Nigeria, from Cambodia in 2010, as well as from Brazil and Puerto Rico from the most recent epidemics.
The results of the study showed that nearly 94% of all pregnancies remained viable when a mock infection was introduced in the first trimester, whereas the viability of fetuses was reduced after the administration of the Zika virus, regardless of the strain used.
The viability ranged from 56% from infection with the Brazil strain to 71% following infection with the Nigeria strain, meaning anywhere from 29% to 44% of pregnancies were lost following infection, according to the study.
When the mice were infected with the virus in the equivalent-to-late-second trimester, the investigators observed fewer miscarriages. The findings suggest that there is less vulnerability to Zika later in pregnancy.
The investigators also observed the activation of antiviral defenses in the placentas of the pregnant mice infected with the Zika virus. They found that the viruses worked like a lock and key, attaching to specific receptors on cells to take hold and spread. Furthermore, the investigators identified receptors on cells in the placenta that the virus may use to cross into the fetus.
The findings suggest that these antiviral pathways could be potential targets for treatments to stop transmission, according to the authors.
Normally, the placenta is organized in discrete layers of tissue, but in mice infected with the virus, the tissue layers became disorganized, which could be how the virus penetrates the fetus.
“This could be why the fetuses in the Zika-infected mice were so vulnerable to either miscarriage or brain damage,” Burd said.
Although the virus appeared to cross the placenta with relative ease during the first trimester, it did not hold true in the second trimester. The direct effects on the pregnancy were much less pronounced if the infection occurred later in pregnancy, according to the authors.
The mouse pups infected with the virus early on in the pregnancy, were more likely to have thinner cortexes and have inflammatory cells in the brain compared with those born to mothers who had a later infection.
The authors noted that some infants born to mothers infected later in the pregnancy still show some ill-effects, but the reasons remain unclear.
In future studies, the investigators hope to determine whether the siblings of the babies born during Zika infection also suffer neurological effects.
“We don’t know if the effects persist in future pregnancies,” Klein said. “We’re just dealing with the here and now. We have no idea what the long-term consequences are for the mother.”