Pitt Forms Zika Research Team

As potential Olympians get ready to compete in Brazil this summer, they’re also preparing to head into the heart of the Zika outbreak.

In early 2016, amidst an increasing number of reported infections across the Americas, the World Health Organization officially declared the Zika virus — a disease spread through mosquito bites — an international emergency.

While it’s not fatal if treated properly, research suggests that contracting the Zika virus during pregnancy can lead to microcephaly, a devastating congenital brain malformation, in newborns.

According to the Estudio Colaborativo Latino Americano de Malformaciones Congenitas, there are typically only two cases of microcephaly for every 10,000 live births in Brazil. Since the Zika outbreak in fall 2015 there have been 1,168 confirmed cases, according to Celina Martelli, researcher at the Fundação Oswaldo Cruz Foundation, or Fiocruz.

Through a program called Cura Zika, Martelli and other members of Fiocruz in Recife, Brazil, have joined with Pitt researchers to confirm the link between Zika and microcephaly, uncover the biochemical mechanisms leading from virus to birth defect and work toward developing a vaccine.

The collaborative group of scientists presented their ongoing research in a symposium earlier this month at the Pitt Graduate School of Public Health. Donald Burke, dean of the Pitt School of Public Health, said the Cura Zika collaboration grew out of a long-standing relationship between Pittsburgh and Recife.

One of the key players linking the two cities is Ernesto Marques, a professor in Pitt’s public health department of infectious diseases and microbiology and a researcher at Fiocruz.

“I knew the University of Pittsburgh should be having more of a global presence,” Burke said. “So we recruited Ernesto [Marques] to come be a faculty member at the Graduate School of Public Health.”

Marques has been at Pitt for seven years, and splits his time between Pittsburgh and Recife, where he runs a tropical infectious disease lab at Fiocruz. Because Marques is from Recife, he has special interest in the city, which flooded the headlines for harboring the virus.

“This is where the epidemic of Zika hit hardest, right in Recife,” Burke said. “So our colleagues … were already on the ground, at ground zero of the Zika epidemic.”

When the epidemic first hit, Burke immediately saw Pitt’s research resources as a possible way to get organized and find funding — Cura Zika was the result.

The Cura Zika team includes Burke, Marques, Martelli, Magee-Womens Research Institute director Yoel Sadovsky and assistant professor of Pitt School of Public Health Jennifer Adibi, all of whom spoke at the symposium on May 5.

“[Zika is the] first infectious disease linked to birth defects in almost 50 years,” Martelli said. “The last one was rubella.”

According to Martelli, 30 percent of pregnant women who tested positive for Zika gave birth to babies with congenital malformations.

Despite this strong correlation, the association between Zika and microcephaly is still so new that no case studies have included the appropriate control groups to test the causal link, Martelli said.

To establish causality, the researchers will compare healthy infants born under similar conditions to infants with microcephaly and then test both groups for Zika exposure.

For the case control study, Martelli recruited 45 healthy infants, matched to 23 microcephaly cases by due date and hospital of birth. The odds of giving birth to a baby with microcephaly were 132 times greater for women who were exposed to the Zika virus compared to women who were not exposed to Zika.

This finding provides strong evidence in favor of the link between Zika and microcephaly, but Martelli still has questions, namely: Why has Zika — a virus identified in 1947 — suddenly become a tremendous public health threat?

According to Marques, Zika originally spread slowly and was only associated with the mild symptoms immediately following infection, including red eyes and skin rash, or often no symptoms at all. Now the spread of Zika is much more rapid and could be the cause of microcephaly.

Marques has two hypotheses to explain the recent increase in virulence.

First, the African strain discovered in 1947 may be more benign than the Asian strain, which is now moving through the Americas, Marques said.

Second, it may be the case that prior exposure to the dengue virus, a mosquito-borne disease that occurs in tropical and subtropical climates, facilitates Zika infection.

This is an important connection because according to Marques, about half the mothers in Recife possess antibodies to dengue 3 virus, a strain also known as DEN-3 SS.

Marques said that research needs to be done on the safety and efficacy of using lived or killed viruses for a Zika vaccine..

“As a long-term goal, we need a vaccine…The same way we needed it for rubella,” Marques said.  Adding that, at this point, there is no “major obstacle” to developing that vaccine. “We can consider that any technology we have available today to produce a vaccine has the potential to work.”

Like the famous historical feud between Jonas Salk and Albert Sabin over the polio vaccine, Marques said there is a debate now between whether a Zika vaccine should use live or killed virus. Research into the safety and efficacy of both methods is needed, Marques said.

According to Yoel Sadovsky, a Pitt professor and scientific director at Magee-Womens Research Institute, time is of the essence. Sadovsky labeled Zika an “emerging human disaster.”

Zika, according to Martelli, is moving faster than dengue in Brazil, where public health initiatives have struggled to control dengue for decades.

Sadovsky is researching the mechanisms by which pathogens pass through the placenta from mother to child.

“The placenta is the conduit from the baby to the outside world,” Sadovsky said.

According to Sadovsky, primary trophoblasts — the placental cells that directly contact maternal blood — are highly resistant to Zika virus transmission. This implies that transmission of Zika to the fetus must occur through a breakdown of the trophoblast defenses, such as pre-existing physical tears or disease states.

All of Sadovsky’s cell cultures were derived from mature placentas, which has lead Adibi to wonder if trophoblast cells extracted earlier in pregnancy are less resistant to Zika.

Adibi said that while it is well-known that the placenta changes dramatically as pregnancy progresses, it is still unknown whether the placenta is more permissive to Zika at different times during pregnancy or whether the timing of Zika infection is important at all for the development of microcephaly.

Adibi and the rest of the Cura Zika team look toward local, international and cross discipline collaborations to answer their plethora of questions.

“My wishful thinking is to have collaboration worldwide,” Martelli said. “I think infectious disease can be a global threat for everyone.”