Think of a developing brain the way you might think of constructing a house. First you need the physical structure—the foundation, floors, support beams, a roof—and then you add plumbing, ductwork, and wiring.
The cell division that happens in a developing fetus’s brain, particularly in the first trimester of pregnancy, is the structural stuff.
But brain development isn’t done after the first trimester, or even when a baby’s born, says Forrest Gulden, a scientist in Yale University’s department of neuroscience. “A lot of what’s happening throughout infancy, childhood, and adolescence is basically building the wiring.”
For researchers focused on how the Zika virus affects the human brain, one of the central questions has to do with timing: When is Zika most dangerous, and why?
Zika is unlike some viruses linked to birth defects—like rubella—which become far less risky to a fetus after the first trimester. Though especially dangerous early in pregnancy, Zika can continue to cause bad outcomes for fetuses well into the third trimester of pregnancy.
Since the brain is still developing even when a baby is born, how dangerous is a Zika infection to a newborn, or to a toddler?
This isn’t an easy question to answer because researchers are only just beginning to understand the mechanics of the virus. In very early brain development, for instance, Zika can cause the birth defect microcephaly—in which babies are born with abnormally small heads—because the virus diverts a key protein necessary for neural cell division, a crucial part of building the structure of the brain. The diversion happens as part of an immune response, as the body tries to fight off infection, but the result is that neural progenitor cells, key building blocks of the brain, don’t divide to form the brain’s structure as they otherwise would. That’s according to research by a team of researchers at Yale, who published their findings in the journal Cell Reports last month.
That important cell division takes place in a fetus in the first trimester—which is why, he says, the risk of microcephaly is higher earlier in pregnancy.
“If a Zika infection happens in the first trimester, it’s devastating,” says Andre Sousa, a neuroscientist at Yale and one of the authors of the Cell Reports paper. “It’s really, really bad. The more you go toward adulthood, the less severe the symptoms are, but Zika still might even paralyze [a person who develops Guillain-Barré syndrome as a result of the virus] and we’ve seen it can kill a person.”
In other words, certain health risks associated with Zika may dissipate as a person gets older, but others may emerge. Mature neurons seem less vulnerable to Zika than developing brain cells, but at least one study—which focused on mice, not humans—found the virus can still damage adult brains.
That may be because mice, unlike humans, still have a significant pool of neural progenitor cells well into adulthood, whereas “this is more debatable in humans,” Sousa says. “We think that after 1 year-and-a-half—after 18 months of age—there are no more actively dividing neural progenitors [in the human neocortex]. Up to 18 months, Zika probably can still affect these progenitors and have some effect in the brain, but this will be very small because most of the brain is already formed.”
But Sousa and his colleagues underscored that Zika remains a concern even once babies are born. “An early newborn brain may be very susceptible to an infection by Zika,” says Marco Onorati, a neuroscientist at Yale. That’s because Zika doesn’t just affect brain cells, but can also infect blood vessels in the brain, he says.
Given the huge jump in microcephaly cases following the Zika outbreak in Brazil,
much research has focused on how Zika infections affect babies before they’re born. Still, as the Centers for Disease Control and Prevention points out on its website, many of the effects of prenatal Zika infection on a baby remain unknown.
Even less is known about how Zika—particularly the seemingly more aggressive strain of the virus associated with the latest outbreak—might affect people infected as babies or children. "Research on this topic is just beginning,” David Vu, a pediatric infectious disease specialist at Stanford Medicine, told NPR in June.
Scientists say it’s reassuring that there have been few reports of serious health problems among Zika-infected toddlers—brain infections, like encephalitis, are possible but seem to be rare. For now, the scientific consensus is that Zika is riskiest to pregnant women. And, like adults, some 80 percent of children infected with the virus are asymptomatic—meaning they’ll never even know they had it.