Albert Osterhaus, a virologist at the University of Veterinary Medicine Hannover in Germany, thinks that developing an animal model—in addition to in vitro and post-mortem studies—is necessary to show that maternal infection with Zika virus can actually cause microcephaly. After that, scientists can start to use the model to probe the underlying mechanisms.

Osterhaus, who has written about the mechanisms by which neurotropic viruses can cause neuropathology13, speculates that one way the virus might infect the fetal brain is via the bloodstream. When a pregnant woman is infected with Zika virus during her first trimester, the virus could move into her bloodstream and cross into the placenta, enter the fetus's bloodstream and travel to its developing brain where it could interfere with normal growth. “But to be honest, we don't know that,” he says. His lab currently has plans to develop an animal model.

Several other researchers are also trying to model the infection in mice and in nonhuman primates, something that scientists attempted in the 1950s14 and 1970s. A series of experiments conducted in the early 1950s by George W.A. Dick—the scientist who originally discovered Zika—found that although young mice were susceptible to Zika infection when the researchers administered the virus via an intraperitoneal injection, the older mice were not. Mice of all ages were susceptible, however, when given the infection intracerebrally15. In 1971, T.M. Bell and colleagues infected newborn and young adult mice via an intracranial injection. They observed necrosis in neurons within the hippocampus, inflammation, enlarged glia and active viral replication16.

Fearful Flavivirus: A molecular model of the Zika virus. Credit: Evan Oto/Science Source

Even if some researchers have been able to model Zika infection in mice, however, mice are not a perfect model system for microcephaly because their brain development differs fundamentally from that in humans. Arnold Kriegstein, director of the developmental and stem cell biology program at the University of California, San Francisco, points to a pool of founder cells called radial glia as one key difference17. Humans have more—and more types—of radial glia than do mice, and these in turn give rise to more neurons in the human brain than in the mouse brain. Gene mutations and viruses that could destroy these founder cell populations might therefore result in more severe microcephaly in humans than in mice, Kriegstein explains.

Garcez will try to model vertical transmission of Zika by using an intraperitoneal injection to deliver the virus to pregnant mice. She then plans to assess if brain development changes in the pups of infected mothers.

Meanwhile, Duarte dos Santos plans to inject several clinical isolates of the virus into mouse models to determine whether and, if so, how Zika virus causes birth defects. These models include transgenic AG129 mice, which have deficient anti-viral cytokine responses and thus are susceptible to dengue infection18. Ann Powers, chief of the alphavirus laboratory at the US Centers for Disease Control and Prevention, adds that scientists at her institution will also use AG129 mice, in addition to outbred, wild-type mice.

At the California National Primate Research Center, Koen van Rompay has been studying HIV in nonhuman primate models since the early 1990s. With the emergence of Zika as an infectious disease of global concern, he is now expanding his focus to model the virus in rhesus macaques. Macaques, he explains, are seasonal breeders—which means that he will need to infect them soon to study how maternal infection affects the fetal brain. Otherwise, he will have to wait months until the next breeding season. Consequently, he is scrambling to pull together enough pilot funding for his research team to infect the breeding females in the next one or two months. Van Rompay hopes that if they are able to recapitulate infant microcephaly via maternal infection with Zika virus in the macaques, they will then be able to ask questions about the mechanisms and test the safety and efficacy of potential vaccines and interventions.

“All of us here are volunteering our time for this, but we feel that this is the reason that we became scientists,” he says. “When there is some acute disease, or some acute emergency—this is why we got our training.”