For the first time, researchers have confirmed that the Zika virus indeed causes birth defects — in mice, anyway. After deliberately infecting pregnant mice, they found that the pups were born with brain damage and slightly abnormally small heads, a condition called microcephaly.
This is the first study to directly prove that the virus causes birth defects, the study authors write in Nature. The virus appears to have crossed the placenta, restricting the pups’ growth — and not just in their heads, either, but all over their bodies. The animal model may help researchers aiming to develop vaccines, or treatments that could prevent pregnant women from passing the virus to their developing child.
This is the best evidence to date that Zika causes the developmental disorder
In October 2015, Brazilian public health officials first warned of an increase in microcephaly, following a Zika outbreak in the country last year. Since the outbreak, reports of microcephaly have spiked in Brazil, with almost 5,000 confirmed or suspected cases. Though several case studies have shown the Zika virus in fetal brain tissue, this is the best evidence to date that Zika does, in fact, cause the developmental disorder.
"This is an extremely important study because it demonstrates for the first time that Zika virus infection of a pregnant female leads to fetal abnormalities," Andrew Pekosz, professor of molecular microbiology and immunology at Johns Hopkins Bloomberg School of Public Health, who did not take part in the study, said in an email. "Up until this study, all the data suggesting this has been correlative — meaning we have a large number of cases of fetal abnormalities in humans that are associated with Zika virus infection. What we have lacked is direct proof that infection leads to fetal abnormalities and this study provides that."
Last month, the US Centers for Disease Control and Prevention reviewed the existing data on Zika-related birth defects and concluded that the virus is indeed linked to microcephaly. That conclusion, however, was early, says Alysson Renato Muotri, the associate director of the Stem Cell Program at UCSD School of Medicine and one of the study authors. It used clinical and epidemiological evidence, but it didn’t test the link in an animal model. "I think it was too premature to claim that there was a causation," he says.
Today’s study provides the evidence. The researchers infected two groups of pregnant mice with the Brazilian strain of the virus, isolated from a Zika case in northeastern Brazil in 2015. When the researchers analyzed the pups right after birth, they found not only that one group of newborns had slightly smaller-than-normal heads, but also that their whole bodies hadn’t grown as much as they should have. The virus had crossed the placenta in that group, the researchers found.
Researchers found that the Zika virus crosses the placenta
The fact that the Zika virus gets across the placenta is key, according to Eric Rubin, an immunologist at Harvard University who did not take part in the study. Only a few pathogens are known to do that. Now, with this animal model, we have a way of examining how that happens. "That’s pretty important," Rubin says, "because now you can ask, ‘how does this happen, why does it happen, and are there places where we can intervene to stop it from happening?’"
Surprisingly, a second group of Zika-infected mice used in the study didn’t give birth to pups with birth defects — so in this group, the virus didn’t cross the placenta and infect the pups. That may be because the second group of mice was slightly different, genetically, than the first. Their immune systems may have been strong enough to fight the virus, Muotri speculates. The differences between the two groups may help explain why some people infected with Zika don’t pass the infection to their children. A study published in March in The Lancet showed that women who become infected with the virus during the first three months of pregnancy have a 1 in 100 chance that their fetus will develop microcephaly. That’s higher than usual — but most people do have normal children.
"The fact that some mouse strains don’t show fetal disease after infection but some do allows for a study of the genes that might control the susceptibility to fetal disease," Pekosz said in an email.
The study could help in the development of a vaccine or drug to treat Zika infections
Other than testing the effects of the Zika virus in the mice, today’s study also showed how the virus can infect human brains to induce the microcephaly. The researchers used tiny clusters of human brain cells made from stem cells that mimic how the brain develops to determine this. They exposed these brain cell clumps to two strains of Zika virus, one from Africa and one from Brazil. The researchers found that, just like in the mouse pups, the virus kills brain cells and causes the cerebral cortex to be much thinner, impairing brain development. The effects were much stronger with the Brazilian strain of the virus than the African strain. "The Brazilian virus is definitely more aggressive," Muotri says.
This part of the study wasn’t as groundbreaking, because two recent papers had already revealed the effect of the Zika virus on human brain cells. So today’s breakthrough is really that the researchers tested the effects of Zika on mice, creating an animal model that can now be used to develop a vaccine or a drug to treat the disease.
That’s the ultimate goal. Rubin says there are reasons to be optimistic, given all the studies that have come out about Zika in just the past few months. "This is really I would say a scientific triumph," he says. "Academic science doesn't tend to be very nimble, but in this case there’s been a very very rapid response."