The viruses that cause dengue fever and Zika fever have established themselves as formidable forces of devastation. About 390 million dengue infections occur globally each year, and 3.9 billion people worldwide—over half the human population—are at risk of infection. Zika is newer to the scene, but infections have already been reported in at least 86 countries.
Though neither disease carries a particularly high fatality rate, it appears that these stealthy viruses are capable of leaving their mark on a person long after they’ve vacated the body—in a way that could affect the health of generations to come.
Today, in the journal Cell Host & Microbe, two new studies report that dengue and Zika viruses may be exploiting a loophole in the human immune system that enhances the severity of both diseases. In the first article, a group at the La Jolla Institute for Immunology shows that having a mother who survived Zika may inadvertently worsen the symptoms of dengue in young offspring; in the second, researchers from Emory University indicate that fetuses with mothers previously infected with dengue virus may be at a higher risk of acquiring Zika through the placenta.
The viruses that cause dengue and Zika are closely related, making it easy for the human body to confuse one for the other. This results in a bait-and-switch: When one of these viruses is misidentified, it’s able to conscript the body’s own immune molecules into ushering the pathogen into a susceptible cell. Because dengue and Zika viruses often run rampant in the same geographic regions, especially in the Americas, the new findings underscore the lasting effects of outbreaks, but could also inform the development of future vaccines.
“These are both really great studies,” says Jean Lim, an immunologist at the Icahn School of Medicine at Mount Sinai who was not involved in the research. “They’re really adding important clues about Zika and dengue, and how preexisting immunity impacts another virus.”
Normally, when a virus infects a human, the immune system dispatches a cavalry of neutralizing antibodies—Y-shaped molecules that recognize a specific feature of the pathogen, latch onto its surface, and block it from infecting cells. The virus, now coated with a cluster of antibodies, is then swallowed whole and destroyed by white blood cells. If the same virus ever tries to set up shop in the body again, the immune system will recall previous infections and rouse the same set of antibodies to nullify the threat before it can do any significant damage.
But dengue has a bad reputation for refusing to play by the rules. Many different subtypes of this virus exist, and surviving infection with one subtype doesn’t guarantee protection from another. In fact, these subsequent viral encounters can often be far worse than the first. When neutralizing antibodies that have been trained on one dengue subtype run up against another many years later, two issues may arise. First, the virus is just different enough that antibodies will bind poorly to its surface. Second, antibody levels eventually wane in the body, and there are fewer around to put the virus out of commission.
As a result of these dips in quality or quantity, the antibodies that confront the new virus fail to disarm it—and when white blood cells arrive on scene to clean up the mess, dengue is gobbled up in a still-active form. From here, the virus will replicate and destroy the immune cell, perpetuating the cycle of infection. This phenomenon, in which antibodies become a composite Trojan horse that unwittingly chauffeurs viruses into these vulnerable cells, is called antibody-dependent enhancement.
To make matters worse, antibody-dependent enhancement doesn’t just cause problems for individuals infected with multiple strains of dengue. As they develop, fetuses inherit antibodies from their mothers through the placenta. These antibodies stick around throughout the first year or so of life as the offspring develop their own immune systems. But if their mothers happened to have even a glancing blow with dengue, babies can be at high risk for developing severe dengue if they’re infected with a different subtype in the months after birth, while their bodies still contain maternal antibodies.
So when a very similar-looking virus called Zika began causing serious outbreaks a few years ago, researchers like Sujan Shresta, an immunologist at the La Jolla Institute for Immunology and senior author of the first study, began to worry. Zika belongs to the same group of viruses as dengue—flaviviruses—which also include the nasty pathogens that cause West Nile fever, yellow fever, and Japanese encephalitis. If Zika was popping up in the same areas as its infectious cousin, Shresta reasoned, the same-same-but-different concept of antibody-dependent enhancement could spell trouble for the countless individuals and their children exposed to both viruses.
Shresta and her colleagues, led by immunologist Angela Fowler, decided to test if a mouse mother’s previous Zika infection could worsen dengue symptoms in her offspring. The researchers infected two groups of mouse pups with Zika: one set born to mothers who had been previously infected with Zika virus, and the other born to mothers who hadn’t. They found that the first group of pups had acquired Zika antibodies from their mothers, and were consequently protected from Zika infection, showing that the antibodies were active against their intended target. But when the team repeated their experiment, this time exposing the pups to dengue, the antibodies were instead weaponized by the new virus: The pups who had inherited Zika antibodies suffered more severe dengue symptoms and were more likely to die from the infection.
When the researchers next assessed the ability of these maternal Zika antibodies to subdue dengue, unsurprisingly, they weren’t up to snuff. While the antibodies were able to attach to dengue, they did nothing to neutralize it. Instead, they seemed to do the opposite, ferrying the virus into the arms of unsuspecting cells.
“The antibody responses to these viruses are highly complex,” Shresta explains. “One infection can affect subsequent ones, and in this case, the antibody response to Zika has an enhancing effect on dengue.”
And the problem of mistaken identity between dengue and Zika could be a two way street. In the second study, Mehul Suthar and Matthew Zimmerman, immunologists at Emory University, led a team of researchers in testing this possibility.
One of the most dangerous aspects of a Zika infection is the virus’ ability to cross a mother’s placenta into her fetus, often leading to severe birth defects like microcephaly. If dengue antibodies have a nasty tendency to guide similar-looking viruses into cells, it’s possible a placental Zika infection could be exacerbated by this inappropriate immune response, endangering a child before it’s even born.
Unlike the previous study, which used mice, Suthar and his team conducted their experiments on human placental immune cells. When the researchers introduced only Zika to the cells, very few viruses took hold—but if they added dengue antibodies to the mix, the antibodies stuck to the viruses and shepherded them into the cells, where Zika quickly multiplied. This could be a clear-cut way for Zika to pass easily from mother to child, explains Zimmerman, “as if the virus is hitching a ride on a normal, physiological system.”
A preexisting dengue infection is by no means necessary for Zika to have devastating effects on a developing fetus, Suthar says, and antibody-dependent enhancement is unlikely to be the only way Zika traverses the placental barrier. However, the researchers’ experiments highlight a subtle way Zika can hijack the body to some potentially devastating ends. Millions of women worldwide harbor low levels of dengue antibodies in their blood from prior exposures—and because infections are often asymptomatic, many of those interested in having children may be unaware of just how vulnerable their fetuses could be to Zika.
Of course, neither mice nor donated placental tissue is a perfect stand-in for a human. For instance, mice often have to be genetically manipulated to become susceptible to dengue virus, explains Rebecca Christofferson, an infectious disease expert at Louisiana State University who did not contribute to the new findings. Additionally, antibody-dependent enhancement is often easier to show in cells growing in a dish than in the body of a living animal. But simply raising the possibility of one virus feeding off the dregs of the response to another could make a huge difference in preventing future outbreaks.
The new findings may also affect how researchers counteract these diseases in the future. Infections aren’t the only ways a body can generate antibodies—vaccines for either dengue or Zika would induce their production as well. Vaccine safety may need to be re-evaluated in areas where both viruses are prevalent, explains Sallie Permar, an immunologist at the Duke University School of Medicine who did not participate in the research, so that protection against one disease doesn’t accidentally exacerbate another. Still, this doesn’t invalidate vaccination in the fight against these pathogens: Rather, with the issue of antibody-dependent enhancement in mind, some of the most effective vaccines of the future might be carefully concocted mixtures of strong, neutralizing antibodies active against multiple flaviviruses.
And far more than the potential synergy between dengue and Zika may be at play, Christofferson points out. There’s limited evidence that other flaviviruses like Japanese encephalitis virus might also augment the severity of future dengue infections, but it’s still unclear how widespread antibody-dependent enhancement really is outside the lab. More research is needed—and now that more and more countries harbor multiple flaviviruses, Shresta explains, the urgency of understanding these threats is greater than ever.
The critical next experiments will be epidemiological studies in humans, says Sharon Isern, a virologist at Florida Gulf Coast University who was not involved in the studies. Such future work will be challenging, requiring large numbers of people and extensive clinical history, but reports like these underscore the importance of human-centric follow-up.
“Animal models provide good information,” Isern adds, “but the answers are in large human populations.”