Three groups of scientists reported Wednesday that fetal mice infected with Zika showed brain damage, a finding that confirms the prevailing view that the virus can disrupt the development of fetal brains in humans and provides a clearer avenue to study the problem.
The work should put to rest lingering doubts in some quarters that the Zika outbreak sweeping through Latin America and the Caribbean is responsible for a surge in babies born with microcephaly and other brain anomalies, said Nikos Vasilakis, a virology expert who was not involved in these studies.
“Let me put it bluntly: These are game changers,” said Vasilakis, an associate professor of pathology at the University of Texas Medical Branch in Galveston. “We need to move forward now.”
Two of the studies showed that mice can be used to explore the effects of Zika infection during pregnancy. The third reported on what was observed when Zika virus was injected directly into the brains of fetal mice.
Dr. Michael Diamond, the senior author of one of the studies, said the research shows that Zika alone is sufficient to cause the brain malformations being seen in Brazil, and to a lesser degree, in several other countries. Some researchers had speculated that Zika was contributing to an unexpectedly high rate of side-effects only because it was spreading in a population in which a large number of people had previously been infected with other, related viruses.
But Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases, said the main benefit of the new studies is that they show mice can be used as an animal model for Zika infection in pregnancy.
Mice are easy to work with, and the short duration of their pregnancies makes it easier to study how viruses affect them than conducting the same studies in some other animals, including primates.
Fauci, whose institute funded Diamond’s work, said as far as he is concerned, it was already clear Zika infection in pregnancy was leading to brain damage in babies in some cases.
“I don’t think you need a mouse model to prove that,” he said. “I think the mouse model is very valuable as a tool to study pathogenesis” — the way the virus wreaks its damage.
Mice are not normally susceptible to the Zika virus, so the research teams had to take some special steps to get the infection to take root.
Diamond and colleagues at Washington University in St. Louis reported in the journal Cell that they had developed two different mice models. In one, the scientists genetically modified the mice to render their immune systems defective. They suppressed the immune systems of another type of mice by giving them injections of an antibody.
A second team of researchers, from Brazil, reported in the journal Nature that they used an extremely high dose of Zika virus to successfully infect the pregnant mice they used.
Both teams were then able to see what damage the virus caused.
Diamond’s team noted placental insufficiency, a condition in which blood flow to the fetus is inadequate. The same phenomenon has been seen in human pregnancies following Zika infection.
The Brazilian scientists, led by Patricia Beltrão-Braga of the University of São Paulo, said they did not study the placentas. But they did see intra-uterine growth restriction — less growth in the fetus than is normal. That, too, has been reported in fetuses carried by women infected during pregnancy.
They noted that when the virus moved into the brain, it killed cells and led to a thinning of brain tissue. Diamond’s team also saw the virus in the fetal brain, though at lower concentrations than were found in the placenta. That meant his team could not detect which types of brain cells the virus attacked.
The Chinese researchers, who published their findings in Cell Stem Cell, reported the virus targeted a key type of cell in fetal brains, called neural progenitor cells. The developing brains actually shrunk.
Diamond’s laboratory worked with a virus that was isolated during the 2013 outbreak in French Polynesia; the team from Brazil used a virus from there, taken from an infant born with microcephaly, Beltrão-Braga said.
Her group also worked with a virus from Africa, isolated in 1947, when Zika was first discovered. There are two strains of Zika virus, the African variety and the so-called Asian strain, which was responsible for the outbreak in French Polynesia and is the virus racing through the Americas.
Beltrão-Braga said comparison of the effects of the two strains in cell culture experiments supports the theory that the Asian strain is more virulent. But Vasilakis and others cautioned against drawing that conclusion from this work, saying the version of the African strain the Brazilian team worked with has been used for so long in mice that it has adapted to them. It is not reflective of the Zika viruses currently circulating in Africa.
“It’s an ancient virus. It’s not relevant anymore,” Vasilakis said, though he admitted there are other clues that suggest the Asian strain may be more dangerous.
“There’s a kernel of truth there, but it’s too early to conclusively infer that unless further research is being done,” he said.
Diamond’s team is now using its mouse models to look for answers to Zika questions. For instance, researchers are trying to see if infection at different times during pregnancy leads to different outcomes. In this work, they infected the mice at what is the equivalent of the end of the first trimester of a human pregnancy.
The Brazilian team infected their pregnant mice at a point equivalent to the second trimester of human pregnancy.
Diamond said the mice can also be used to test experimental vaccines and drugs that might mitigate the effects of Zika infection. But he cautioned that while mice can provide some clues, there are limits to what can be learned from them.
“The way we look at it is the mouse allows us to develop hypotheses and test them,” he said. “However the conclusions are going to need to be corroborated in humans. Because mice are not humans.”
