The usually benign virus is confounding scientists. What’s it going to take to solve the problem? A Q&A with tropical diseases expert Duane Gubler.

How can a 70-year-old virus known not for its pathogenicity but for its relatively benign nature, suddenly be linked to birth defects and a devastating autoimmune disorder?

That’s the Big Scientific Question confronting public health authorities after two major outbreaks of Zika, a virus spread by the same Aedes aegypti mosquitoes that transmit yellow fever, dengue fever and chikungunya virus, broke out in Brazil and French Polynesia. The developing story is dominating the headlines, with frequent updates about the potential risks posed by a once ignored virus. Much of it is speculation at this point, but evidence is starting to accumulate that Zika may indeed have caused a spike in the number of infants born with microcephaly—a rare birth defect characterized by abnormally small heads and extensive brain damage. Scientists found traces of the virus in brain and other tissue in two infants with microcephaly who had died shortly after birth; viral particles were also detected in the amniotic fluid of two mothers who miscarried. Other case reports reached somewhat similar conclusions, though results have not been validated or published.

Epidemiologists in Brazil and French Polynesia, where an outbreak occurred in 2013-2014, are also investigating a possible connection between Zika and 163 cases of Guillain-Barré Syndrome, a rare neurological condition that causes paralysis and is sometimes fatal. The syndrome has been known to occur following vaccination, most famously in 1976 when over 500 people who received a swine flu vaccine developed Guillain-Barré.

There are now public health alerts cautioning women living or visiting Zika hotspots to not get pregnant and warning men who have traveled to these areas and who have a pregnant partner to abstain from sex or use a condom during the duration of the pregnancy.

Still, the Zika question is going to be a tough one to answer. Unlike more studied viruses like yellow fever or dengue, Zika is, biologically speaking, something of a blank slate for the scientific community. Virologists research the major health threats. Zika never fit that mold and so never attracted the kind of attention or funding that malaria, HIV or yellow fever did. There are no institutes named for it, no therapeutics and no vaccines to treat or prevent it. Researchers don’t know how exposure to Zika in utero might be preventing fetal brains from developing normally, or, for that matter, if the flavivirus is even responsible for the rise in birth defects. Malnutrition, exposures to drugs or alcohol or certain infections, such as rubella and cytomegalovirus, can trigger microcephaly, but most causes are unknown.

Epidemiologists in Brazil are also struggling to determine what the actual incidence of microcephaly is both now and before. Until last year, the number of reported cases in Brazil was, on average, less than 200. Since then, over 4,700 suspected cases of microcephaly have been reported, and 404 confirmed. Interpreting these numbers can be difficult, though, because the screening tools clinicians use to define microcephaly are not consistent. The suspected number of cases of microcephaly may also be distorted due to increased awareness of the condition.

To get some historical perspective on this tropical disease and on flavivurses in general, Eureka turned to Dr. Duane Gubler, an internationally recognized expert on flaviviruses who has spent his entire career working on tropical infectious diseases, particularly dengue and dengue hemorrhagic fever. Gubler is the Founding Director of the Emerging Infectious Diseases research program at the Duke-NUS Medical School in Singapore and previously chaired the Department of Tropical Medicine, Medical Microbiology and Pharmacology at the University of Hawaii’s John A. Burns School of Medicine. He was also Director of the Division of Vector-Borne Infectious Diseases at the US Centers for Disease Control and Prevention (CDC), and chief of the CDC’s Dengue Branch. Here are Dr. Gubler’s edited responses. The interview was conducted by Senior Scientific Writer Regina McEnery.

Q: Why have we heard so little about Zika until now?Dr. Duane Gubler

DG: No one was studying it. We’ve known about Zika for 70 years, but it was never considered a public health problem, let alone a major public health problem. There was a minimal amount of work done on it in the early days in Africa, and since then it has sort of been an observation that pops up occasionally but that no one paid any attention to. It occurred throughout Asia and Africa, but it’s been sporadic and silent. There has never been any severe disease associated with it. In this regard, it’s very similar to the West Nile virus before that vector-borne disease was introduced into the US.

Q: How did Zika emerge?

DG: It came out of a Rockefeller Foundation study in the 1930s and 1940s. The foundation, in the 1930s, had set up several labs in Latin America, India and Africa to study yellow fever. One of those labs was in Entebbe, Uganda. Yellow fever had already been documented in the Amazon basin in [a large animal species] and the group wanted to find out if it was occurring in Africa as well. The scientists had caged [animals] in the Zika Forest that they were using as sentinels. One of the animals came down with a febrile illness, so they took the blood, inoculated it in mice, and it killed the mice. Follow-up neutralization studies found that it was not a yellow fever. They also isolated the virus subsequently from mosquitoes, and that was how Zika became known.

Q: Is Zika dramatically different from other flaviviruses?

DG: Zika is a flavivirus in the Spondweni clade genetically separated from yellow fever and dengue . Clinically, it was thought to be a milder viscerotropic virus, but with the documentation we are getting on Guillain-Barré and microcephaly it may turn out to be neurotropic as well.

Q: Do you think Zika is the cause of the microcephaly?

DG: It’s all speculation at this point. I think there is a good correlation with the Zika epidemic and microcephaly. There is some epidemiologic and virologic evidence that supports an association, but it has not been documented conclusively. And [scientists] will have to do a lot more work before it is shown to be a cause and effect. The only way to complete Koch’s postulates is with an animal model to do some pathogenesis studies. It’s not going to be easy to actually accomplish that.

Q: How would you prove a cause and effect?

DG: To infect females of an animal model during various stages of pregnancy, then study how Zika virus affects the fetuses.

Q: Are there other mosquito-borne viruses that cause microcephaly?

DG: Most of the neurotropic arboviruses cause meningoencephalitis but microcephaly is an atypical clinical presentation. Guillain-Barré is associated with a lot of different viruses, including dengue. Guillain-Barré is more of an autoimmune type of thing that we don’t fully understand.

Q: So the microcephaly connection is really rare and unusual for any virus?

DG: Yes, this is why it’s caused so much attention. And we don’t have any antiviral drugs or vaccines to treat or prevent Zika, so what we really need to do now is intensify mosquito-control efforts. The problem is we don’t have the infrastructure or any good or new tools to control them. The most successful control program was in the 1950s and 1960s, when we eliminated Aedes aegypti mosquitoes from 22 countries and effectively controlled epidemic yellow fever and epidemic dengue. Top down paramilitary organizations with highly trained, disciplined field inspectors went house to house treating properties with DDT and getting rid of larval habitats. It successfully prevented epidemic disease transmission and policy makers couldn’t convince themselves to continue the funding, so it was disbanded in the early 1970s.

Q: Are you part of any collaborations taking up Zika now?

DG: Yes, very much so. In fact I helped start a whole new program two years ago designed to take advantage of new technologies that are in the pipeline that can be used to control dengue and other Aedes aegypti-borne diseases. It was originally targeted for dengue but we are expanding it to other mosquito-borne diseases as well.

Q: What are some of these new technologies?

DG: There are new vaccines in the pipeline for dengue and there will be for Zika and chikungunya in the next few years. There is a lot of interesting work being done on antiviral drugs that inhibit flavivirus replication. People are developing monoclonal antibodies that can be used for passive transfer and perhaps prophylaxis use. And there are a number of new mosquito control tools also in the pipeline that should be available in the near future. These include new residual insecticides, and uses for insecticides such as spatial repellants, lethal ovitraps, insecticide-treated materials, etc. Finally, new genetic and biological control methods show good promise. Unfortunately, none of these tools will be effective when used alone, but if we combine selected methods that can be used synergistically, we can increase herd immunity and decrease mosquito populations to the point where transmission rates will hopefully drop.

Q: Finally, do you think too much attention is being showered on Zika?

DG: I’m biased of course. I think the attention Zika is getting highlights a tremendous hole in our public health arm, which is effective mosquito control. This problem doesn’t just relate to Zika. It extends to dengue, chikungunya as well as yellow fever, which I think is a time bomb waiting in the wings. The attention we are seeing with Zika is an indication that these kinds of epidemics can and do occur and that we ought to be using some of the resources to be proactive and preventive rather than reactive. We are a crisis-oriented society. We go from one crisis to another and waste a lot of money reacting. If we used that money for developing broader infectious disease prevention and control programs, then perhaps we could prevent some of these epidemics or at least detect them early enough to contain them before they spread.

(Photo of Dr. Gubler provided by Duke-NUS)

How to cite:

McEnery, Regina. Zika’s Dark Side. Eureka blog. Feb 9, 2016. Available: http://eureka.criver.com/zikas-dark-side/