A little over a year ago, global health officials issued an epidemiological alert for the seemingly mild Zika virus, a pathogen transmitted by mosquitos. Typically adults infected with the virus have moderate symptoms—rashes, fever, joint pain, malaise. But since October of 2015, when the virus began its march through Brazil, reports of infants born with microcephaly began pouring in. This birth defect causes smaller than average heads and a range of neurologic disorders.
Yet until now, there was no experimental evidence that directly linked Zika with microcephaly, and debate swirled about whether the incidence was merely coincidence. But a study published this week in Nature, provides the first experimental evidence that Zika can cause microcephaly in mice. The paper also provides clues to show how the virus can cross the placenta and alter the brain growth of a developing fetus.
"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," Andrew Pekosz, a professor at Johns Hopkins Bloomberg School of Public Health, who was not involved in the new work, tells Alessandra Potenza at The Verge. "What we have lacked is direct proof that infection leads to fetal abnormalities and this study provides that."
Between October 22, 2015 and March 26, 2016 there were 944 confirmed cases of microcephaly and other central nervous system defects in Brazil and an additional 4,291 cases suspected, writes David A. Schwartz of the Medical College of Georgia in an expert commentary for the publishing group SpringerNature. Brazil typically fewer than 200 cases of microcephaly each year, reports Kerry Grens for The Scientist.
"We stopped all of our research just to work with Zika virus," says study co-author Patricia Beltrão Braga of the University of São Paulo, Brazil, in a podcast discussion with Kerri Smith from Nature. Braga's colleague, immunologist Jean Pierre Peron, did the same.
Previous work had uncovered the virus hiding in the human central immune system, but that evidence wasn't enough to show cause and effect. Last month, scientists with the Centers for Disease Control and Prevention declared that Zika was responsible for severe birth defects, including an abnormally small head and brain. But the declaration was based on the numbers of Zika and microcephaly cases, not experimental confirmation.
So the researchers infected of pregnant mice with the disease. And sure enough, the pups they bore later not only showed brain abnormalities, but they were also smaller overall.
The team discovered that the virus seems to target cells that should be dividing and causes them to self-destruct. They were even able to identify a handful of genes related to cell death that appeared to be promoted or suppressed by the viral infection. Notably, a second mouse strain the researchers tested didn't show this connection, a finding that suggests some people might be more or less susceptible to the virus's effects. The difference might be in individuals' immune systems, the researchers write in the paper.
The team also compared a strain of the Zika virus from Brazil to a strain from Africa in human brain stem cells. The African strain didn't kill as many cells as the Brazilian strain, suggesting that the latter likely has mutations that made it more aggressive.
Results from mouse testing, however, are notoriously difficult to scale up to humans. So the researchers also tested human "mini-brains"—structures grown from human stem cells that resemble the layers of a human brain. The mini-brains can provide more information about how growth and development might be altered in human subjects. The mini-brains infected with Zika didn't grow normally or as well. And again, the Brazilian virus appeared to be more potent than the African one.
People in Africa and Asia have dealt with the presence of Zika since at least the 1950s without the birth defects, writes Macon Morehouse for Science News. It's possible those populations built up a kind of immunity. But when the virus spread to Brazil and French Polynesia, the incidence of birth defects started to rise.
"[This] suggests that the Brazilian strain has, somehow, adapted to humans." study co-author Alysson R. Muotri of the University of California School of Medicine says in a press release. "We are investigating how genetic differences might cause that difference." By identifying tweaks in the Brazilian Zika virus' genes has that make it more dangerous, the team could find some weakness to exploit and prevent the damage it causes.
The new results emphasize that the Zika threat is greater than microcephaly—namely widespread cell death and the restricted growth of the mouse pups. Researchers worry that the Zika virus could cause a host of other long-term problems of which we aren't yet aware.
"The media focuses on microcephaly because the images are quite dramatic," says Muotori in the podcast. "But our data suggests that other tissues are affected, so this is basically the tip of the iceberg."