The-Scientist: Does Prior Dengue Exposure Help or Hurt a Zika Infection?

The mosquito-borne Zika virus that recently spread rapidly throughout the Americas shares many characteristics with another virus: dengue. Both are flaviviruses, which are enveloped, sphere-shape virions that are typically transmitted by mosquitos and ticks. Due to their structural similarities and because the latest Zika outbreak appeared in dengue-endemic regions, scientists have been investigating whether antibodies against one might be able to react to the other—and whether these interactions could either worsen or buffer against infections.

Researchers had previously demonstrated a phenomenon known as antibody-dependent enhancement (ADE)—where, at certain concentrations, antibodies against one virus can heighten the effects of another—between different types of dengue viruses. This suggested that antibodies against other flaviviruses might possess similar features. “When the recent Zika outbreak occurred, one of the major questions scientists had was whether or not the enhancement effect could also impact Zika infections,” says Jean Lim, a virologist at the Icahn School of Medicine at Mount Sinai in New York. “Because of the potential for Zika to cause damage during pregnancy, this was—and still is—an important question.”

Early in vitro studies confirmed that dengue antibodies extracted from human blood cross-reacted with Zika, and some suggested that they could strength infection. “There were a lot of people who hypothesized that, perhaps the reason that Zika is causing microcephaly was because you were getting enhancement,” Aubree Gordon, an epidemiologist at the University of Michigan, tells The Scientist. “So there was a lot of interest within the entire field to look at if you see protection or enhancement.”

In animal models, scientists have reported that dengue antibodies can both neutralize and enhance Zika. While the latter observation has raised concerns about heightened Zika infections in regions where dengue is common, the epidemiologic data have been more reassuring. To date, large, human cohort investigations have only found protective effects against Zika. Still, some scientists say that it is possible that augmentation may occur—and recent experimental studies in human tissues and mice suggest that this may happen in pregnant females.

Dengue antibodies: friend or foe?

Earlier this year, two long-term assessments of populations in Central and South America reported that dengue immunity was protective against subsequent Zika infections. One study, published in Science, examined a cohort of 1,453 residents in Brazil and found that having dengue antibodies prior to the Zika outbreak was tied to a decreased risk for Zika infection and fewer symptoms in those who contracted the disease. The other, published in PLOS Medicine, followed a group of approximately 3,700 children in Nicaragua, and also discovered that dengue immunity protected against symptoms of Zika, although this study did not find a reduction in total infections.

“We expected that we would see protection,” says Gordon, who is a coauthor of the Nicaragua study. “We thought we might see enhancement at well—but at this point we don’t have any evidence for it.”

Gordon’s anticipation that dengue antibodies might both hurt and help Zika infections came from prior laboratory experiments and epidemiological investigations that found the effects of cross-reactivity are concentration-dependent, at least when it comes to multiple dengue infections. In humans, Gordon and her colleagues have observed that high levels of antibodies against one type of dengue buffers against another, but lower levels actually enhance disease in subsequent exposures.

According to Lim, the same may apply for dengue-Zika interactions. The fact that high concentrations of dengue antibodies offer protection in humans suggests that at the other end of the spectrum, at lower concentrations, you might see enhancement, she explains. “If you saw no protection, then there’s no potential for enhancement.”

Lim’s group has found evidence that dengue antibodies could enhance Zika infection in mice. But other groups—who have used various different animal models and experimental protocols—have turned up mixed results. “It’s still a very contentious field. Some groups see enhancement effects and other groups do not,” Lim says. “I think everybody is open to the idea that it could happen, but the data is not clear at this point.”

Gordon agrees that it is too early to rule out the possibly that enhancement is happening. “The fact that we do see protection does make me a bit more concerned, in fact, that enhancement could occur as well, because it verifies that there certainly is an interaction.”

Identifying whether ADE occurs is particularly important for current efforts to develop Zika vaccines, notes Albert Ko, a physician and epidemiologist at the Yale School of Public Health and an author of the Brazil cohort study. “The question is, are the antibodies made by a dengue or Zika vaccine friend or foe” to subsequent infections, he tells The Scientist. “Obviously we have to be cautious, because there are these studies in mice and in vitro that find enhancement, but in humans we don’t see enhancement signals as of yet.”

Pregnancy-specific effects

One of the biggest concerns about Zika is the virus’s ability to cause microcephaly and other severe birth defects. “Zika is a mild disease, but the big public health impact is when pregnant women get affected,” says Ko. “How the prior dengue antibodies influence Zika when a pregnant woman is infected—and how that would influence vertical transmission from the mother to the fetus is an open question.”

Although researchers have yet to find an answer in cohorts of people, recent work in human tissues and animal models provides hints that ADE may indeed influence the spread of Zika from a pregnant mother to her developing fetus. This work may still be preliminary, but “the big picture that’s emerging is that these cross-reactive antibodies look like they’re facilitating Zika virus [transmission] across the placenta,” says Mehul Suthar, an immunologist at Emory University.

Several groups, including Suthar’s, have found the Zika virus can infect cells in the placenta, an organ that serves many functions during pregnancy, including providing an immunologic barrier between the mother and her developing fetus. Last year, Suthar and his colleagues reported in Cell Host & Microbe that dengue antibodies could enhance Zika in human placental tissue and macrophages, the primary cell type infected by the virus. They also found that this process was dependent on Fc receptors, proteins that are involved in transcytosis, the process of trafficking molecules across the placenta.

Two recently published rodent studies also support this theory. One, which appeared in Immunity and was conducted by Lim and her colleagues, found that in pregnant mice, pre-existing dengue antibodies enhanced Zika virus replication in the placenta and caused inflammation and injury to the organ. “We think that Zika, in the presence of dengue antibodies, is really causing damage to the placenta,” Lim says. “And that this is indirectly causing damage to the developing fetus.”

In the other study, published last month in Science Advances, immunologist Ashley St. John and her team at the Duke-NUS Medical School in Singapore reported that the presence of dengue antibodies in pregnant mice led to enhanced transmission of Zika viruses to their fetuses.

Although both rodent studies found enhanced Zika infection in the placenta of dengue-immune mice—and that enhancement effect was dependent on Fc receptors—the Singapore team observed microcephaly-like effects on fetuses while the other group did not. According to St. John, this is likely because her study used mice that had their immune systems intact and Lim’s used immunocompromised mice (the later model is a common practice when experimenting with Zika and dengue infections because rodents are more resistant to the viruses than humans). However, “fetuses don’t survive Zika infection in the immunocompromised system, so our system allows us to actually study fetal development,” she adds.

Future studies in humans and nonhuman primates will be necessary to verify that this process really occurs. “I do think there is potential for dengue to enhance Zika virus infection,” Lim says. “The real test will be to see whether or not this happens in humans.”