A new report raises questions about whether contracting Zika virus in the months after birth may damage an infected newborn’s brain.
Researchers at Emory University injected a small number of infant rhesus macaques with the virus five weeks after birth—an age which roughly correlates with Zika exposure in three-month-old human babies—and found that although the monkeys cleared the infection from their blood as expected, the animals developed brain damage and behavioral problems.
“This is the first time [infant infection] has been studied in a controlled fashion. And while it is with a small group of animals, it does make us more concerned about what the long-term behavioral or cognitive issues may be in human infants that might have been similarly exposed,” says Ann Chahroudi, senior author on the study and an assistant professor of pediatrics at Emory University School of Medicine.
The good news is infected monkeys did not develop the most severe problems seen in humans exposed to Zika prenatally, which include limb deformities, hearing and vision loss, and a small-headed condition that can form in the womb called microcephaly. Yet certain brain areas typically responsible for vision as well as emotional and behavioral responses did not develop normally in infant macaques exposed to Zika, and the animals acted strangely in behavioral tests compared with control animals not exposed to the pathogen. Connections between the amygdala and hippocampus were also weak in the infected macaques, which suggests signals sent between those two areas—ones that would help the infants recognize and respond to stressful situations—would be slow or spotty.
During testing, the infected infant animals did not act normally when faced with certain threatening scenarios. The study authors believe this was because the animals had trouble processing that they should be concerned. In particular, the infected monkeys did not freeze as they typically would when feeling threatened and expressed less hostility and anxiety in stressful situations than did animals not infected with Zika. The findings, from researchers at Emory and several other institutions, were published Wednesday in Science Translational Medicine.
The study involved eight monkeys. Two of the animals served as controls and were not injected with the virus but the remaining six were given a single injection of a Zika strain similar to the one that has circulated in Brazil in recent years. Four of the infected monkeys were euthanized in the days and weeks following infection for tissue and immunological analyses. But two of the monkeys were studied until they were a year old. Researchers periodically scanned the brains of these two and administered visual memory tests (that involved eye tracking) during the first six months of life. Later they examined the macaques’ reactions to stress by testing how they responded to the presence or stare of a human stranger—one dressed in an Al Gore mask. The way Zika acted in the brain generally fit with what is already known about the pathogen’s biology and how it attacks that organ.
One of the few bright spots from the test results was that the infected animals’ memories did not appear to be damaged; they performed as well as controls in standard visual recall tests. Still, Chahroudi cautioned that more subtle issues with memory and behavior may only become apparent later in the monkeys’ lives—a situation analogous to testing in human children, which is more informative when done on school-age kids instead of toddlers. The authors also noted another area of potential concern: Prior monkey research has shown macaques with early-life hippocampal damage go on to demonstrate schizophrenia-like characteristics in adolescence. This raises questions about what the long-term effects of similar damage may be for the mental health of those exposed to Zika in infancy.
“We don’t really have any data yet to back this up but it is a suggestion that should be considered,” says Karin Nielsen-Saines, a pediatric infectious diseases specialist at the University of California, Los Angeles, who studies Zika and was not involved in the macaque study. “We’re not sure what triggers development of schizophrenia and I don’t think we can jump from ‘Monkeys develop this,’ to ‘Kids with Zika early in life will develop schizophrenia or other psychiatric conditions’—that’s a bit of a leap,” she says. Steve Goldman, a professor of neurology at the University of Rochester Medical Center also urged caution due to the small number of tested monkeys and added that the brain damage was too nonspecific to point to a condition like schizophrenia at this stage. Generally, harm to the hippocampal-amygdala circuit, he says, may be linked to mental conditions including autism spectrum disorder and anxiety disorders. But if the Zika infection occurs after birth and the monkey findings hold in humans, it is possible children’s brains would still be able to correct for any potential damage and be perfectly healthy, he adds.
In light of the new macaque findings, Nielsen-Saines says she will be changing what she tells parents who ask whether they can bring a young child to an area where the disease has become endemic. “Usually we tell parents there is not much data there, but now we can say there is an animal study saying there may be neurodeficits later—so if you could not travel with your children in the first six months of life, maybe that would be a better option.”
Although Nielsen-Saines called the new Zika findings “alarming,” she underscored that they are not yet definitive for humans. In particular, the number of monkeys was small and there may be differences between macaques and humans that could affect how the body processes the infection. It is also possible the inoculum—the amount of virus included in the subcutaneous shot the monkeys received—may not truly correlate with the amount present in one or a few mosquito bites. It is not known what the viral dose of Zika from a mosquito blood meal may be, Chahroudi says, but her team used a dose believed to approximate a mosquito bite, based on previous studies with other mosquito-borne diseases from the same family as Zika.
Researchers and clinicians still do not have any conclusive answers about the possible health effects of Zika exposure early in life, partly because such studies require careful tracking and testing to determine if children were infected in the womb or after birth. Moreover, many infected people are asymptomatic so it can be difficult to find kids with the disease. Doctors are aware of several instances in which babies acquired Zika virus via breast-feeding, but there have not been any reported health problems from that exposure.
The National Institute of Allergy and Infectious Diseases hopes to get a better picture of the long-term results from Zika exposure during infancy in the next few years, and recently funded a study that will examine the effects of acquiring the disease after birth among infants and young children in Guatemala. Its leaders aim to enroll approximately 1,200 individuals and monitor their health outcomes with further testing.
Scientists know human infant brains are far from fully developed. During the first year of life, human babies learn to focus their vision, reach out, explore and learn about the things around them. Our brains also roughly double in size during that time and harm to this organ can be particularly disastrous.
Chahroudi says her team is interested in repeating aspects of its work but wants to try infecting macaques later in their first year of life. The goal, she says, is to see “if there is a window of time after which we don’t see these same findings.”