Zika: Not Just Yesterday’s News

Zika virus may have left the headlines, but research on it has continued at P&S since the first stories broke about the virus and its effects on fetuses.

In 2015, the world learned of birth defects in Brazil apparently caused by a previously obscure pathogen called Zika virus. Several nations issued travel advisories telling pregnant women to avoid visiting the affected area, but airline travel and the ubiquitous tropical mosquito Aedes aegypti quickly spread the virus throughout the Americas. 

The epidemic captured the interest of many at P&S, with its long history in tropical medicine and strong ties to Latin American communities in New York and abroad. Within months of the first reports linking Zika to microcephaly, P&S researchers and physicians scrambled for grants, enlisted the aid of a movie star, reached across departmental boundaries, and began Zika virus projects that ranged from the clinical to the molecular.

Some of the newly minted Zika researchers had little choice; the virus came to their doorstep. “It was horrifying in a way that I would not otherwise have thought about,” says Stephen Nicholas, MD, professor of pediatrics. Dr. Nicholas, who founded and directs the Program for Global and Population Health, has been caring for pregnant women in the Dominican Republic since 1999, and the Zika virus epidemic looked terribly familiar to him.

In 2013, Chikungunya virus, also spread by Aedes aegypti, moved across South America and into the Caribbean. In nine months, the virus infected about 70 percent of the population of the Dominican Republic before the epidemic subsided. Reading about the Brazilian Zika virus outbreak and its apparent link to microcephaly, Dr. Nicholas said, “I started seeing the pattern which headed straight to the Caribbean, and I knew what was going to happen.” One of his Dominican programs cares for about 700 pregnant teenagers each year. 

Like other researchers and physicians, Dr. Nicholas gave himself a crash course in Zika virus. A member of the Flavivirus genus, which also includes West Nile and Dengue viruses, Zika was first discovered in 1947 in Africa. Because human cases seemed to be either asymptomatic or mild, the virus garnered little interest from medical researchers. Public health officials and virologists noted its spread from Africa to Asia, then French Polynesia, but it did not seem as threatening as other vector-borne viruses. 

Scientists develop a model to study both normal and virally disrupted brain development.

That changed when Zika reached Brazil, and a huge increase in cases of microcephaly followed. A flurry of studies on humans, animal systems, and cell cultures soon revealed that the correlation was not spurious. Zika virus can and does infect and damage brain tissue, and developing fetuses seem particularly susceptible. 

But the virus does not always invade the nervous system. Many women have delivered unaffected children after being infected with Zika virus during pregnancy. When another Zika outbreak happened in 2016 in the same region of Brazil, microcephaly rates stayed flat. Outbreaks in other parts of the Americas have shown similar variation; sometimes Zika virus infection is inconsequential, sometimes it is life-altering. What determines the outcome?

That question fascinates Vincent Racaniello, PhD, the Higgins Professor of Microbiology & Immunology. “Our interest has been viruses that get into the central nervous system, how they get there, what they do there.” Having spent most of his career studying poliovirus and closely related enteroviruses, he quickly pivoted his attention to Zika. Dr. Racaniello was approached by Richard Vallee, PhD, professor of pathology & cell biology, whose lab had long studied microcephaly, and David Doobin, an MD/PhD student working in Dr. Vallee’s lab.

Dr. Vallee uses fetal rat brain slices to study live neuronal behavior during development. This system allowed the group to address not only which cell types were susceptible to Zika infection, but also the consequences for progenitor cell proliferation and migration. Amy Rosenfeld, PhD, a research associate in Dr. Racaniello’s lab, and Dr. Doobin addressed these issues in a joint project. Rat brain slices, the standard for this work, are not susceptible to Zika virus infection, so the team adapted the system to use fetal mouse brains instead. The result is an elegant model for both normal and virally disrupted brain development. “In an uninfected brain slice you see these lovely fibers just like railroad tracks going from the ventricle to the surface of the brain; when you infect the culture with Zika, after two days or so these tracks are now all twisted and tangled,” says Dr. Racaniello. “That disrupts neuronal migration and derails development of the neocortex, mimicking microcephaly.” One important outcome of this work so far is evidence that, despite the very recent discovery of Zika pathogenesis in the brain, East Africa Zika isolates from as early as 1947 also interfere with development in the group’s organotypic culture system. 

Most isolates of Zika virus seem equally capable of derailing neural development in brain slices, arguing against the idea that the virus itself somehow changed in Brazil. That suggests some other factor, possibly co-infection with another virus or some combination of environmental or genetic triggers, may drive Zika-associated birth defects. 

Dr. Racaniello would like to continue studying Zika, but funding has been challenging. “When we started we didn’t have funding for Zika, but we had a grant to study enterovirus D68, so we used that money,” he says, adding that the NIH is flexible about letting researchers explore other areas. The NIH and other federal agencies have begun grant programs specifically for basic research on Zika, but competition is fierce.

Funding has been no easier in clinical research. As the epidemic spread through his Dominican patient population, Dr. Nicholas scrambled for help to study it. “All the funding, what little there was, was with the CDC, and their emphasis was Puerto Rico,” he says. He resorted to personal fundraising. “I went to every friend I knew who had two pennies to rub together and asked for help.” Contributors included a well-known movie actor with ties to the Dominican Republic and other connections to P&S.

The resulting prospective study in La Romana, Dominican Republic, began enrolling patients in January 2017 to track Zika virus infection, serology, and development in pregnant women and their babies. The goal is to see whether the epidemic in the Dominican Republic—which has infected about 20 percent of the country’s population—affects the rate of birth defects. Fundraising for year two of the program is underway.

— Alan Dov